TYPE Review

PUBLISHED 10 May 2024

DOI 10.3389/fphar.2024.1385479

Inflammation and cancer: friend

OPEN ACCESS or foe?
EDITED BY
Chiara Bolego,
University of Padua, Italy Andrés David Turizo-Smith 1,2, Samantha Córdoba-Hernandez 2,
REVIEWED BY
Lidy Vannessa Mejía-Guarnizo 3,4,
Gabriela Cristina Fernandez, Paula Stefany Monroy-Camacho 4 and
National Scientific and Technical Research
Council (CONICET), Argentina Josefa Antonia Rodríguez-García 4*
Lucia Conti,
1
National Institute of Health (ISS), Italy Doctorado en Oncología, Departamento de Patología, Facultad de Medicina, Universidad Nacional de
Colombia, Bogotá, Colombia, 2Semillero de Investigación en Cannabis y Derivados (SICAD), Universidad
*CORRESPONDENCE Nacional de Colombia, Bogotá, Colombia, 3Facultad de Ciencias, Maestría en Ciencias, Microbiología,
Josefa Antonia Rodríguez-García, Universidad Nacional de Colombia, Bogotá, Colombia, 4Grupo de investigación en Biología del Cáncer,
[email protected] Instituto Nacional de Cancerología, Bogotá, Colombia
RECEIVED 12 February 2024
ACCEPTED 22 April 2024
PUBLISHED 10 May 2024

CITATION Chronic inflammation plays a crucial role in the onset and progression of
Turizo-Smith AD, Córdoba-Hernandez S,
Mejía-Guarnizo LV, Monroy-Camacho PS and
pathologies like neurodegenerative and cardiovascular diseases, diabetes, and
Rodríguez-García JA (2024), Inflammation and cancer, since tumor development and chronic inflammation are linked, sharing
cancer: friend or foe? common signaling pathways. At least 20% of breast and colorectal cancers are
Front. Pharmacol. 15:1385479.
doi: 10.3389/fphar.2024.1385479
associated with chronic inflammation triggered by infections, irritants, or
autoimmune diseases. Obesity, chronic inflammation, and cancer
COPYRIGHT
© 2024 Turizo-Smith, Córdoba-Hernandez,
interconnection underscore the importance of population-based interventions
Mejía-Guarnizo, Monroy-Camacho and in maintaining healthy body weight, to disrupt this axis. Given that the dietary
Rodríguez-García. This is an open-access inflammatory index is correlated with an increased risk of cancer, adopting an
article distributed under the terms of the
Creative Commons Attribution License (CC BY).
anti-inflammatory diet supplemented with nutraceuticals may be useful for
The use, distribution or reproduction in other cancer prevention. Natural products and their derivatives offer promising
forums is permitted, provided the original antitumor activity with favorable adverse effect profiles; however, the
author(s) and the copyright owner(s) are
credited and that the original publication in this
development of natural bioactive drugs is challenging due to their variability
journal is cited, in accordance with accepted and complexity, requiring rigorous research processes. It has been shown that
academic practice. No use, distribution or combining anti-inflammatory products, such as non-steroidal anti-inflammatory
reproduction is permitted which does not
comply with these terms.
drugs (NSAIDs), corticosteroids, and statins, with plant-derived products
demonstrate clinical utility as accessible adjuvants to traditional therapeutic
approaches, with known safety profiles. Pharmacological approaches targeting
multiple proteins involved in inflammation and cancer pathogenesis emerge as a
particularly promising option. Given the systemic and multifactorial nature of
inflammation, comprehensive strategies are essential for long term success in
cancer therapy. To gain insights into carcinogenic phenomena and discover
diagnostic or clinically relevant biomarkers, is pivotal to understand genetic
variability, environmental exposure, dietary habits, and TME composition, to
establish therapeutic approaches based on molecular and genetic analysis.
Furthermore, the use of endocannabinoid, cannabinoid, and prostamide-type
compounds as potential therapeutic targets or biomarkers requires further
investigation. This review aims to elucidate the role of specific etiological
agents and mediators contributing to persistent inflammatory reactions in

Abbreviations: NSAIDs, non-steroidal anti-inflammatory drugs; BAX, Bcl-2-associated protein X; CRC,

colorectal cancer; COX, cyclooxygenase enzymes; ECs, endocannabinoids; gp130, glycoprotein 130; IL-
6, interleukin-6; IL-10, interleukin-10; JAK, janus kinase; NF-κB, nuclear factor-κB; MMP, matrix
metalloproteinases; STAT, signal transducer and activator of transcription; STAT3, signal transducer
and activator of transcription 3; TAM, tumor-associated macrophages; TME, tumor microenvironment;
TNFα, tumor necrosis factor-α; HPV, human papillomavirus.

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Turizo-Smith et al. 10.3389/fphar.2024.1385479

tumor development. It explores potential therapeutic strategies for cancer

treatment, emphasizing the urgent need for cost-effective approaches to
address cancer-associated inflammation.

KEYWORDS

chronic inflammation, cancer, obesity, immune cells, cannabinoids, endocannabinoid

system, non-steroidal anti-inflammatory drugs

1 Introduction systematically restore the physiological condition of the affected

area. However, the course of inflammation can deviate towards a
Inflammation, particularly chronic inflammation, plays a pivotal chronic course when this regulatory mechanism is disrupted,
role in the onset and progression of various chronic pathologies impeding the resolution process. In such instances, the persistent
including neurodegenerative and cardiovascular diseases production of proinflammatory molecules and the ongoing
(Stephenson et al., 2018; Becatti et al., 2018), diabetes (Turkmen, recruitment of inflammatory cells contribute to a chronic state,
2017), and cancer (Murata, 2018). Breast and colorectal cancer this prolonged inflammation hampers the re-establishment of tissue
(CRC) are the most prevalent types of cancer worldwide homeostasis, underscoring the complexity and potential
(Harbeck and Gnant, 2017), with a significant incidence and consequences of dysregulated inflammatory responses (Sugimoto
mortality rates (Sung et al., 2021). At least 20% of cancers are et al., 2016).
linked to chronic inflammatory processes triggered by factors such Tumor development is associated with a chronic inflammatory
as infections, exposure to irritants, or autoimmune diseases process, as inflammation and cancer both engage common signaling
(Table 1) (Crusz and Balkwill, 2015). pathways (Barabutis et al., 2018). This review aims to elucidate
After successfully resolving the acute phase, the tissue specific etiological agents and mediators that can initiate persistent
remodeling process begins, aiming to reinstate physiological inflammatory reactions contributing to the development of tumors.
conditions. Inflammation, a physiological response, acts as a Additionally, the exploration will encompass viable therapeutic
defense mechanism against pathogens and facilitates tissue repair strategies designed for cancer treatment, improving our
once the triggering agent has been eliminated. Inflammatory understanding of the interplay between inflammation and
response is dynamic and can manifest as an acute, self-limited tumorigenesis.
process that effectively restores tissue homeostasis, by generating Presently, cancer treatments are prolonged and often involve
cellular determinants and locally active inflammatory mediator several adverse effects. Moreover, their exorbitant costs render
molecules (Gupta et al., 2018a). them inaccessible to more than 80% of the global population
Following the effective resolution of the acute phase, a (Gupta et al., 2018a), Consequently, there is an imperative need
subsequent stage of tissue remodeling is initiated to to explore novel cost-effective therapeutic approaches for

TABLE 1 Summary of risk factors and inflammatory conditions associated with cancer development and estimated new cases around the world. Globocan,
2020.

Type of cancer. International classification of New estimated cases Inflammation related risk factors
diseases for oncology (ICD) Globocan 2020
Colorectal 1.931.590 Obesity, sedentary lifestyle

C18-21 tobacco use, alcohol consumption, inflammatory

bowel disease

Breast cancer C50 2.261.419 Obesity, tobacco use, sedentary lifestyle, alcohol
consumption

Lung C33-34 2.206.771 Tobacco use and exposure to environmental pollutants

Stomach C16 1.089.103 H. Pylori infection, obesity, alcohol consumption

Pancreatic C25 495.773 Tobacco use, chronic pancreatitis, diabetes, obesity

Liver 905.677 Hepatitis B and C virus

C22 infection, alcohol consumption, obesity

diabetes, tobacco use

Leukemia C91-95 474.519 Obesity, tobacco use, human T-cell lymphotropic virus
type 1 (HTLV-1) infection

Uterine cervix C54 604.127 Human papillomavirus (HPV) infection

Source: Adapted from (Todoric et al., 2016; Ferlay et al., 2021).

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Turizo-Smith et al. 10.3389/fphar.2024.1385479

addressing the inflammatory phenomena associated cell lines such as HT-29, leading to over-regulation of BAX and IL-
with cancer. 10 expression and downregulation of Bcl-2 expression, inducing
apoptosis, and inhibiting cell growth (Chen et al., 2017; Del Carmen
et al., 2017). Furthermore, the microbiome’s composition influences
2 Inflammation and cancer: a complex responses to chemotherapy and immunotherapy (Iida et al., 2013;
problem with no simple answers West and Powrie, 2015). In murine melanoma models,
Bifidobacterium significantly improves the response to anti-PDL1
It is now well-established that the presence of inflammatory cells immunotherapy (Sivan et al., 2015), and Bacteroides enhances the
precedes tumor development (Colotta et al., 2009; Thompson et al., effectiveness of anti-CTLA-4 therapy by stimulating the immune
2015). Given that all tumors exhibit an inflammatory infiltration, response (Vétizou et al., 2015).
chronic inflammation is widely recognized as a hallmark of cancer Notably, inflammation observed in cancer patients
(Grivennikov et al., 2010; Hanahan and Weinberg, 2011; Capece demonstrates dysregulation and increased production of
et al., 2018; Paul, 2020). Carcinogenesis linked to factors such as inflammatory agents like proteases, eicosanoids, cytokines,
tobacco use, pathogenic infections, and exposure to irritants like chemokines, and acute-phase inflammatory proteins that enter
asbestos (Colotta et al., 2009; Thompson et al., 2015) explains the the circulation. Evidence suggests that immune cells produced
impact of inflammatory processes on tumor development. many proteins, in broad quantities, regulating immune cells
Inflammation promotes the acquisition of tumor cell function under inflammatory conditions. Protein altered serum
characteristics such as apoptosis suppression, uncontrolled levels were observed in CRC patients compared to controls.
growth, tumor dissemination, and immune evasion (Colotta (Table 2) (Hanahan and Coussens, 2012; Candido and
et al., 2009; Thompson et al., 2015). The inclusion of Hagemann, 2013; Tuomisto et al., 2019a). Evaluating the serum
Inflammation as a distinctive feature of cancer stems from the profiles of 13 cytokines, chemokines, and growth factors in 116 CRC
pivotal role played by inflammatory cells in tumor development patients and 86 healthy controls revealed an increased expression of
(Hanahan and Weinberg, 2011). IL-6, IL-7, CXCL8, IL-8, and PDGFB and decreased serum
Through the action of proinflammatory agents such as CCL2 levels (Kantola et al., 2012; Jin et al., 2014; Xu et al., 2016).
histamine, growth factors, cytokines, and free radicals, among Here, a concise overview is provided of some inflammatory
others, vascular permeability increases, creating a favorable cytokines and modulators that could serve as potential targets for
environment for cancer development (Nagy et al., 2008). anticancer therapy, along with their potential involvement in
Cigarette smoking has been linked to a significant reduction in inflammation-associated carcinogenesis.
the activity of superoxide dismutase and glutathione peroxidase
enzymes in erythrocytes, decreasing antioxidant defense
mechanisms and increasing the cellular vulnerability to oxidative 2.1 Interleukin-6 (IL-6)
stress and damage associated with reactive oxygen species,
potentially leading to carcinogenesis (Caliri et al., 2021). IL-6, a pleiotropic cytokine, is produced by various immune cells
The status of the human microbiome emerges as a risk factor (monocytes, macrophages, T and B lymphocytes), epithelial,
influencing the development and outcome of various cancers fibroblast, glia, adipocytes, and tumor cells within the tumor
(Aarnoutse et al., 2019; Lucas et al., 2017). It is well known that microenvironment (TME) (Taniguchi and Karin, 2014a; Crusz
the human gastrointestinal system hosts approximately and Balkwill, 2015). Notably, Ras-induced IL-6 secretion within
1,000 species of microorganisms, which maintain symbiotic the TME actively promotes tumor growth in vivo (Ancrile et al.,
relationships with the host (Qin et al., 2010; Lucas et al., 2017), 2007). IL-6 exhibits both pro- and anti-inflammatory actions
performing metabolic, immunological, and protective functions. An contributing significantly to tumor development. Adipose tissue
imbalance in its composition (dysbiosis) has been linked to chronic is a major source of IL-6, accounting for approximately 30% of
inflammatory diseases (Lucas et al., 2017). Numerous studies reveal circulating IL-6. This association explains the heightened cancer risk
alterations in the microbiome composition of patients with colon and poor prognosis associated with obesity (Kolb et al., 2016;
adenomas, suggesting a role for dysbiosis in the initial stages of CRC Tuomisto et al., 2019a). Given that the clinical management
development (Shen et al., 2010; McCoy et al., 2013) and intestinal practices for cancer patients are similar regardless of weight,
barrier dysfunction (Yu and Fang, 2015; Vipperla and Keefe, 2016). understanding the mechanisms through which obesity influences
Adopting healthy lifestyle including sound dietary consumption cancer initiation and progression becomes crucial for developing
is fundamental for inflammation prevention, especially when precise therapies tailored to obese cancer patients.
coupled with factors such as obesity (Kolb et al., 2016) and In experimental models of carcinogenesis, IL-6 activity,
cardiovascular disease (Becatti et al., 2018), which are closely mediated by signal transducer and activator of transcription
associated with chronic diseases and cancer development 3 STAT3, increases cell survival, and promotes invasion and
(Escobar et al., 2020; Guha et al., 2021), It has been metastasis (Taniguchi and Karin, 2014a; Hirano, 2021a). It has
demonstrated that direct consumption of probiotics and/or been observed that an intriguing inverse relationship between IL-
prebiotics, like lactic acid bacteria, can modulate the development 6 levels and response to treatments such as chemotherapy and
of certain types of cancer. Probiotics, defined as live hormone therapy. This correlation appears to align with a worse
microorganisms, conferring health benefits when administered in prognosis in various cancer types, including ovarian (Kulbe et al.,
adequate amounts (Hill et al., 2014; Lucas et al., 2017; Cheng et al., 2007; Nolen et al., 2008; Anglesio et al., 2011; Kumari et al., 2016),
2020), have been reported to influence colorectal adenocarcinoma hepatocellular (Naugler et al., 2007), and colorectal (Lippitz and

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TABLE 2 Systemic inflammatory markers showing altered circulating levels in patients with CRC.

Acute-phase inflammatory proteins

Marker Function Detection method

C-reactive protein (CRP) ↑ Acute-phase protein ELISA (Enzyme Linked Immunosorbent Assays)

Ferritin ↓ Iron storage Total Reflection X-Ray Fluorescence (TRXRF)

Cytokines and chemokines

IL-6 ↑ Proinflammatory cytokine ELISA

IL-7 ↑ Lymphocyte maturation Magnetic microspheres

CCL2 ↓ Monocyte and macrophage recruitment Multiplex magnetic microsphere assay

CXCL5 ↑ Neutrophil recruitment ELISA

CXCL8 (IL8) ↑ Neutrophil recruitment ELISA and Bio-Plex assay

CXCL10 ↑ T and NK cell recruitment ELISA

Protease enzymes

MMP9 Degradation of extracellular matrix and regulation of neutrophil action ELISA

Growth factors

PDGFB ↑ Mesenchymal cell proliferation Multiplex magnetic microsphere assay

VEGFA ↑ Vascular endothelial growth factor ELISA

Source: Adapted from (Tuomisto et al., 2019b).

Harris, 2016) cancers, among others. These insights underscore the chemotherapeutic agents such as 5-fluorouracil, oxaliplatin, and
significance of unraveling IL-6-mediated mechanisms in cancer paclitaxel by upregulating the expression of anti-apoptotic proteins,
progression and refining therapeutic strategies for improved like Bcl-2 and Bcl-xL (Soleimani et al., 2020), Furthermore, NF-kB
patient outcomes. promotes the expression of proinflammatory cytokines, including
TNFα, IL-6, and IL-1β, elevates levels of angiogenic factors such as
HIF-1α, IL-8, and vascular endothelial growth factors (VEGF), and
2.2 Tumor necrosis factor α (TNFα) facilitates the expression of chemokines, cytoskeleton genes, and
matrix metalloprotease (MMP) (Patel et al., 2018; Martin et al.,
TNFα exerts pleiotropic actions in the regulation of the 2021) all contributing to a microenvironment favorable for metastasis.
inflammatory immune response. The interaction of TNFα with
both TNFR1 and TNFR2 receptors governs the modulation of
cytokines, proteases, and growth factors (Crusz and Balkwill, 2.4 Signal transducer and activator of
2015). In chemically induced models of colitis and CRC, TNFα transcription 3 (STAT3)
produced by mononuclear cells appears to play a pivotal role in
inflammation and subsequent tumor development (Popivanova STAT3 emerges as a pivotal transcription factor involved in
et al., 2008). Therapeutic interventions involving anti-TNFα cancer progression, with its persistent activation fostering chronic
antibodies or TNF receptor fusion molecules have demonstrated inflammation that increases cellular susceptibility to carcinogenesis.
efficacy in genetic models of liver cancer and CRC, although the STAT3 promotes signaling through pro-oncogenic inflammatory
precise mechanism of action of these therapies remains to be pathways, such as NF-kB and gp130/Jak/STAT, leading to
elucidated (Pikarsky et al., 2004; Rao et al., 2006). increased tumor cell proliferation, survival, and invasion while
simultaneously suppressing antitumor immunity (Yu et al., 2009;
Loh et al., 2019). STAT3 plays a crucial role in the carcinogenesis and
2.3 NF-kB tumor progression of various solid tumors, including head and neck
squamous cell carcinoma (Loh et al., 2019) and CRC (Gargalionis
NF-kB, a key regulator of inflammatory events, is associated with et al., 2021), as well as leukemias and lymphomas (Loh et al., 2019).
tumor development and progression (Capece et al., 2018). This
transcription factor orchestrates inflammatory immune responses
and governs various aspects of tumor development, including 2.5 Cyclooxygenases (COX)
inhibition of apoptosis, stimulation of cell proliferation, and
promotion of cell migration and invasion (Ben-Neriah and Karin, COX are enzymes with tumor-promoting activity. They achieve
2011; DiDonato et al., 2012). In CRC, NF-kB hampers the efficacy of this by converting free arachidonic acid (AA) into prostanoids,

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including prostaglandins (PGs) (Wang and Dubois, 2010), which act While numerous studies demonstrate the production of PGE2 at
on tumor cells by inhibiting apoptosis, increasing cell migration, and inflammatory sites, immunoassays quantifying PG have indicated
promoting angiogenesis (Crusz and Balkwill, 2015; Chatterjee et al., non-specific binding to structurally similar compounds such as
2018). The continued overexpression of COX-2 plays a significant PGE2-EA (Glass et al., 2005). Chromatographic methods are
role in promoting carcinogenesis. It does so by increasing the recommended for accurate analyses, as prostamides were initially
expression of carcinogenic reactive oxygen species (ROS) and the misidentified as prostanoids (Woodward et al., 2008; Brown et al.,
production of prostaglandin E2 (PGE2). COX-2 further stimulates 2013; Gouveia-Figueira and Nording, 2015). Notably, prostamides
VEGF through PGE2 promoting angiogenesis and increasing the exhibit a longer half-life compared to prostaglandins. Even though
production of metalloproteinases to favor invasion and metastasis. the latter have substantial biological effects. Prostamide and glycerol
Additionally, it decreases bioavailable arachidonic acid stores, esters as endocannabinoid-derived COX-2 metabolites may be
reducing cell differentiation and apoptosis. Notably, COX-2 stable enough to exert systemic activity (Weber et al., 2004).
inhibits the proliferation of B and T lymphocytes, as well as NK Building up the information provided above, prostamide-type
cells, thereby limiting the antineoplastic activity of the immune compounds emerge as potential biomarkers and therapeutic targets
system (Desai et al., 2018). COX-2 overexpression has been observed for addressing inflammation and influencing adipocyte
in various cancers, including breast, colon, prostate, pancreatic, head differentiation in a coordinated effort to regulate carcinogenic
and neck, skin, and lung (Crusz and Balkwill, 2015; Chatterjee et al., processes. Notably, there is a perspective among some authors
2018; Desai et al., 2018). suggesting that the potential therapeutic advantage of COX-2
Experimental evidence suggests that COX can metabolize inhibitors may, at least in part, stem from their ability to
endocannabinoids, such as 2- Arachidonoylglycerol (2-AG) and diminish or modulate prostamide levels (Woodward et al., 2008).
Anandamide (AEA), into prostaglandin glycerol esters (PG-Gs) and This insight underlines the potential significance of targeting
prostaglandin ethanol amides (PG-EAs), respectively (Kozak et al., prostamide pathways in the development of therapeutic
2002). COX-2-derived metabolites, collectively known as interventions for conditions involving inflammation and
prostamide, represent a novel class of biologically active adipocyte differentiation, contributing to the overall orchestration
eicosanoids. Prostamide modulates cellular functions including of carcinogenic phenomena.
the modulation of IL-2 expression in T cells (Rockwell et al.,
2008), the inhibition of cell growth, and the induction of
apoptosis in CRC cell lines HT29 and HCA7/C29 (Patsos 3 Immune cells associated with tumor
et al., 2005). microenvironment
In contrast to prostaglandins, which are a well-established
potent bioactive lipid messengers derived from arachidonic acid, Immune cells play a pivotal role in maintaining tissue
with extensively studied physiological functions and receptor homeostasis and eliminating pathogens or damaged cells.
signaling pathways, the roles of prostamides remain not yet fully However, in the TME, the dynamics of immune recognition and
understood. Evidence suggests that uridine diphosphate (UDP) cytotoxicity are altered, favoring cell survival, and facilitating tumor
P2Y6 serves as the specific receptor for PGE2-G (Brüser et al., development (Figure 1) (Khandia and Munjal, 2020).
2017). P2Y6 receptor, which under normal physiological conditions Tumor-associated macrophages (TAMs), which represent up to
is expressed in various cell types and tissues, including the spleen, 50% of the tumor mass within the TME, play a significant role in
thymus, intestine, aorta, and leukocytes, plays a crucial role in promoting cell proliferation, suppressing the antitumor immune
maintaining immune functions. It has been shown that response, and enhancing immune evasion and metastasis.
P2Y6 potentiates proinflammatory responses in macrophages and Recruitment of TAMs to the TME from the bloodstream is
exhibits differential roles for the development of atherosclerotic orchestrated by the action of cytokines, chemokines, and growth
lesions, as P2Y6 deficiency can reduce macrophage-mediated factors produced by tumor and stromal cells (Todoric et al., 2016).
cholesterol uptake (Garcia et al., 2014). Typically, macrophages recruited to the TME undergo
Furthermore, the P2Y6 receptor serves as a significant reprograming from an antitumor M1 phenotype to a pro tumor
endogenous inhibitor of T-cell function in allergic pulmonary M2 phenotype, which promotes tumor development (Todoric et al.,
inflammation (Giannattasio et al., 2011). P2Y6 is implicated in 2016; Khandia and Munjal, 2020). In various cancer types, the
increasing IL-1β production and hyperalgesia, in inflammation infiltration of M2 macrophages has been linked to a poor
and macrophage activation (Brüser et al., 2017). While classical prognosis due to their tumor growth-promoting functions. This
PGE2 can reduce the production of proinflammatory cytokines after association has stimulated the exploration of novel therapeutic
lipopolysaccharide (LPS) stimulation, limited information exists alternatives aimed at reducing the infiltration of these cells in the
regarding the ability of prostamide, prostaglandin microenvironment of different tumors both in vivo and in vitro.
E2 ethanolamine (PGE2-EA), to modulate immune responses. Similar to macrophages, neutrophils also play crucial roles in
However, it has been indicated that PGE2-EA, at low modulating tumor behavior, as evidenced by experimental models
concentrations, is pharmacologically active in various smooth and epidemiological studies. Tumor-Associated Neutrophils
muscle tissues and can bind to all four PGE receptor subtypes (TANs) are key components in Cancer-Related Inflammation,
(EP1-EP4), suggesting similar actions to PGE2. Additionally, studies exhibiting versatile functions that can either impede or promote
have shown that PGE2-EA can suppress the inflammatory action of tumor progression. In murine cancer models, neutrophils have been
human monocytes by inhibiting LPS- stimulated TNF-α production shown to respond to TGF-β by acquiring a protumoral phenotype.
(Brown et al., 2013). However, inhibition of TGF-β leads to enhanced neutrophil

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FIGURE 1
Visual representation of the functions of tumor-associated macrophages (TAMs) and tumor-associated neutrophils (TANs) in cancer-related
inflammation underscores their pivotal roles as key regulators of tumor-related inflammatory processes. Neoplastic and stromal cells recruit
macrophages and neutrophils to the tumor microenvironment (TME), directing their polarization towards different phenotypes. Macrophages can
polarize into an M1-like phenotype with antitumor functions under immunostimulatory cytokines such as IFN-γ and TNF-α, releasing TNF-alpha,
ROS, and NO to induce apoptosis and cytotoxicity in cancer cells. Conversely, M2-like macrophages, conditioned by the hypoxic tumor
microenvironment and immunosuppressive mediators (IL-10, TGFβ), exhibit pro-tumor functions. M2-like TAMs secrete molecules promoting
angiogenesis (CXCL8, VEGF), tumor proliferation (EGF, TGF-β, PDGF), induce epithelial-mesenchymal-transition (EMT) (TGFβ), and continuous matrix
remodeling (MMPs, proteases). They also produce various immunosuppressive molecules (IL-10, TGFβ, IDO1/2), which support regulatory T cells.
Neutrophils, under TGF-β induction, can polarize into N1 phenotype, whereas under the influence of type I IFNs, they polarize into N2 phenotype.
Subsequently, N1 neutrophils could inhibit the development of cancer through tumor cell cytotoxicity, tumor suppression (type 1 IFN), and antiangiogenic
effects over the tumor (IFN-β). On the other hand, N2 neutrophils could promote the development of cancer by fostering carcinogenesis and cancer
metastasis [MMPs, oncostatin M (OSM), hepatocyte growth factor (HGF)], tumor growth (NE), and cancer angiogenesis [VEGFs, MMP-1, prokineticin 2
(BV8)], as well as suppressing immunity (arginine depletion).

infiltration into tumors, resulting in heightened cytotoxicity against from M2 to M1, resulting in polyp reduction (Nakanishi et al.,
tumor cells and elevated expression of pro-inflammatory molecules. 2011), highlighting promising avenues for therapeutic
Additionally, neutrophils possess a spectrum of activation states, interventions targeting immune cells within the tumor
including an antitumor N1 phenotype and a protumor microenvironment.
N2 phenotype, in response to signals from the Tumor Figures 2, 3 illustrate the interactions between some
Microenvironment (TME). These findings underscore the inflammatory regulatory agents and their role in carcinogenesis.
complexity of immune cell interactions within the TME and
highlight the potential of targeting neutrophils as a therapeutic
strategy in cancer treatment (Galdiero et al., 2018). 4 Obesity, inflammation, and cancer
Numerous research studies have accelerated the development
of potential therapies, including the use of antibodies like anti- Obesity is an increasing public health problem impacting 35% of
colony-stimulating factor receptor 1 (CSF-1R), which has shown US adults and escalating the risk of numerous cancer types, often
clinical benefits for patients with diffuse multinucleated giant cell correlating with unfavorable outcomes. Central to the progression of
tumors (Mantovani and Allavena, 2015). Moreover, considering chronic conditions is chronic inflammation, characterized by an
that TAMs express substantial amounts of COX-2, experiments in obesity-associated phenotype (Kolb et al., 2016). This inflammatory
animal models of colon cancer, have demonstrated that the use of response initiates with an excessive nutrient intake and manifests in
COX-2 inhibitors such as celecoxib, results in a phenotypic shift specialized metabolic tissues. White adipose tissue adipocytes are

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FIGURE 2
STAT3 (e.g., IL-6) and NF-κB (e.g., IL-17 or TNFα) activators play a crucial role in enhancing the production of proinflammatory mediators, including
IL-6, from non-immune cells such as fibroblasts and adipocytes. This process gives rise to an amplification mechanism known as the IL-6 amplifier (IL-
6 Amp). Through the production of chemokines, IL-6 Amp facilitates the recruitment of immune system cells such as activated T-cells to the site of
inflammation. The dynamic interaction between immune and non-immune cells further reinforces the IL-6 Amp, leading to an increased expression
of genes involved in diverse cellular processes, including cell proliferation, survival, and migration, inflammation, and angiogenesis, among others. This
intricate interplay underscores the significance of STAT3 and NF-κB activation in orchestrating a cascade of events that contribute to the sustained and
heightened inflammatory response within the affected tissue implicated in cancer and chronic inflammatory diseases. Adapted from (Hirano, 2021b).

endocrine cells that secrete a spectrum of cytokines, hormones, and also tends to shift them from an anti-inflammatory M2 phenotype to
growth factors playing a pivotal role in obesity-associated a proinflammatory M1 phenotype (Lumeng et al., 2007), partly due
inflammation (Gregor and Hotamisligil, 2011; Fasshauer and to an imbalance of obesity-related adipokines (e.g., leptin to
Blüher, 2015). Dysregulation of metabolic signaling pathways, adiponectin ratio). This dysregulation, marked by elevated leptin
including NF-κB, c-Jun N-terminal kinase (JNK), nuclear factor production (proinflammatory, pro-angiogenic, and pro-
B, and protein kinase R results from unhealthy lifestyles and proliferative) and reduced adiponectin production (anti-
imbalanced dietary habits (Kolb et al., 2016). inflammatory, anti-angiogenic, and anti-proliferative) (Kolb et al.,
Simultaneously, obesity triggers increased endoplasmic 2016), is associated with an increased risk of colon cancer in men
reticulum (ER) stress, activating of NF- κB and JNK, escalating due to the association with high leptin levels (Stattin et al., 2003;
oxidative stress, and positively regulating proinflammatory Stocks et al., 2008). Leptin has been demonstrated to promote
cytokines (Cnop et al., 2012). All these pathways collectively proliferation, survival, and invasive potential in colon cancer cells
contribute to the initiation of obesity-associated inflammation. by activating MAPK, PI3K, NF-κB, and STAT3 signaling (Rouet-
Although localized in white adipose tissue, this low-grade Benzineb et al., 2004; Uchiyama et al., 2011; Wang et al., 2012).
inflammatory response extends its influence on other tissues like Studies suggest that white adipose tissue macrophages in obese
the liver, pancreas, and brain (Cildir et al., 2013). Furthermore, the individuals express inflammatory cytokines associated with
inflammatory response linked to obesity leads to changes in immune M1 macrophages but lack other M1 macrophage characteristics
cell infiltration and polarization within obese white adipose tissue (Kratz et al., 2014). These macrophages along with adipocytes,
compared with lean white adipose tissue (Han and Levings, 2013). release over 50 different cytokines, hormones, and chemokines,
Macrophages, the primary immune cell population recruited to contributing to the chronic inflammation associated with obesity
white adipose tissue serve as a significant source of proinflammatory (Balistreri et al., 2010; Sun et al., 2011). Inflammation and
cytokines in this context (Weisberg et al., 2003). The adipose tissue inflammatory cytokines play a pivotal role in the development of
of obese individuals not only features increased macrophages but colitis-associated sporadic CRC (Terzic et al., 2010; Moossavi and

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FIGURE 3
The induction of the COX-2 model involves various key processes driven by proinflammatory cytokines, resulting in stimulated cell proliferation and
increased metastatic potential, while also influencing apoptosis and inflammation. Several molecular components participate in this intricate network: Akt
protein kinase B (AKT-PKB), involved in signaling pathways related to cell survival and growth; activator protein-1 (AP-1), pivotal in cellular processes such as
proliferation, differentiation, and apoptosis; cyclooxygenase-2 (COX-2), playing a role in inflammation and promoting cell proliferation; extracellular
signal-regulated kinases 1/2 (ERK1/2), contributing to cell proliferation and differentiation; inhibitor of κB (IκB), regulating inflammatory responses; interleukins
(IL), involved in immune responses and inflammation; lipopolysaccharide (LPS), a component of Gram-negative bacterial cell walls inducing inflammation;
mitogen-activated protein kinase 1/2 (MEK1/2), playing a role in cell proliferation; mitogen-activated protein kinase 3 (MKK3), contributing to cellular
responses; nuclear factor-κB (NF-κB), central to the regulation of immune and inflammatory responses; P38 mitogen-activated protein kinase (P38 MAPK),
involved in cellular responses to stress and inflammation; p53 oncogene (p53), regulating cell cycle progression and apoptosis; prostaglandin E2 (PGE2) with
various physiological effects, including inflammation; peroxisome proliferator-activated receptor γ (PPARG), involved in regulating genes associated with
adipocyte differentiation and inflammation; mitogen-activated protein kinase cascade (Ras/Raf), involved in cell growth and differentiation; tumor necrosis
factor-α (TNF-α), involved in inflammation and immune system regulation; Phosphoinositide 3-kinase, Protein kinase B, and Mammalian target of rapamycin
(PI3K/AKT/mTOR), regulate cell growth and survival; Hypoxia-inducible factor 1α (HIF-1α), controls the cellular response to low oxygen levels; Vascular
endothelial growth factor (VEGF), promotes the formation of new blood vessels; Platelet-derived growth factor (PDGF), stimulates cell growth and
angiogenesis; Dendritic cells (DC), serve as antigen-presenting cells; T lymphocytes (T cells), coordinate specific immune responses against pathogens;
Natural killer cells (NK), are immune cells that target and eliminate infected or cancerous cells; B lymphocytes (B cells), produce antibodies as part of the
immune response; B-cell lymphoma 2 (BCL-2), is a protein involved in regulating apoptosis or programmed cell death; Inhibitor of apoptosis proteins (IAPs),
regulate cell death processes; Survivin is a protein that inhibits apoptosis and promotes cell survival; Vascular cell adhesion molecule 1 (VCAM-1), is involved in
inflammation and immune cell adhesion; Matrix metalloproteinases (MMPs), are enzymes responsible for degrading extracellular matrix components
contributing to tissue remodeling and invasion. COX-2 is also associated with sporadic colorectal cancer development, as well as in familial adenomatous
polyposis and hereditary colorectal cancer, indicating its involvement across different forms of diseases.

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FIGURE 4
Description of the three types of inflammation based on their timing concerning cancer development: Chronic inflammation preceding
tumorigenesis, Inflammation caused by tumor progression and Therapy-induced inflammation.

Bishehsari, 2012). Altered expression of TNF-α, a potent inducer of growth factors, and proteases, collectively referred to as
IL-6, has been observed to promote the development of colorectal senescence-associated secretory phenotype (SASP) (López-Otın
and breast cancer (Sun et al., 2012; Taniguchi and Karin, 2014b). et al., 2013). SASP manifests as an inflammatory dysregulation
Moreover, a plausible link between obesity and increased incidence observed in aged mammals and is associated with tumor
of Estrogen Receptor-positive (ER+) breast cancer in initiation and progression. It contributes to the creation of a
postmenopausal women has been noted, due to elevated favorable TME or directly influences the intrinsic properties of
circulating estrogen levels resulting from increased androgen tumor cells (Morales-Valencia and David, 2021). This revelation
aromatization in adipose tissue (Lorincz and Sukumar, 2006; underscores the intricate relationship between aging, senescence,
Kolb et al., 2016). and cancer development, highlighting the dynamic and
multifaceted nature of these processes.
Several studies have explored the impact of senescence on
5 Senescence cancer initiation. In cellular models of lung (H460), colorectal
(HCT116), and murine breast cancers (4T1), induced
Age stands out as the most significant risk factor for cancer senescence by exposure to etoposide or doxorubicin, resulted
development as evidenced by an exponential increase in the in the renewal proliferation and the formation of tumors when
incidence of most cancers with advancing age (Hsu, 2016). implanted in immunodeficient or immunocompetent mice
This observation suggests the existence of aging-associated (Saleh et al., 2019). B-cell lymphoma models revealed that
factors that contribute to the initiation and progression of cells induced to senesce by doxorubicin exposure exhibited a
tumors. Certain features of aging, including epigenetic more aggressive growth potential compared to non-senescent
changes, mitochondrial dysfunction, and alterations in cells after chemotherapy (Milanovic et al., 2018). Moreover, the
proteostasis, among others, share commonalities with accumulation of senescent cells in adipose tissue, particularly in
characteristics observed in carcinogenesis. Contrary to the visceral fat, has been linked to obesity with obese individuals
initial belief that senescent cells arrested tumor progression having up to 30 times more senescent cells than non-obese
due in part to their characteristic growth arrest, accumulating individuals (Tchkonia et al., 2010; Liu et al., 2019). The presence
evidence indicates that these cells present in higher numbers in of proinflammatory senescent cells in obese individuals holds
older individuals and cancer patients undergoing clinical implications, especially given the substantial size of
chemotherapeutic treatment, remain metabolically active. adipose tissue. This is particularly relevant as obesity-
Moreover, they secrete a combination of inflammatory agents, associated inflammation is known to be linked to cancer

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Turizo-Smith et al. 10.3389/fphar.2024.1385479

incidence and progression. Obese patients express elevated et al., 2014). In CRC, hypoxic stress, and elevated TGFβ levels,
levels of SASP components such as IL-6, IL-8, and TNF-α, favor the differentiation into regulatory T-cells (Treg cells)
reflecting the increased levels observed in older adults suppressing effector T-cell differentiation and affecting antitumor
(Morales-Valencia and David, 2021). immunity (Westendorf et al., 2017; Schmitt and Greten, 2021).
Forms of inflammation in carcinogenic development can be
categorized based on their timing in cancer pathogenesis: 1) chronic
inflammation preceding tumorigenesis, 2) inflammation caused by 5.3 Therapy-induced inflammation
tumor progression, and 3) therapy-induced inflammation
(Figure 4). Tumor cells interact with their microenvironment, This is an unintended consequence of therapy rather than its
comprising immune and stromal cells to suppress immune objective; but it plays a decisive role in determining therapeutic
responses, while inflammatory processes shape the immune response and the probability of relapse, exhibiting potential
pathogenesis of cancer. antitumor or protumor effects, depending on the specific context.
Following therapy, tumor cells, undergo necrosis, releasing damage-
associated molecules, or neoantigens, which recruit and activate
5.1 Chronic inflammation preceding antigen presenting cells (APCs) (Schmitt and Greten, 2021) which
tumorigenesis are capable of presenting neoantigens to T-cells and activating de
novo responses and enhance immunosurveillance (Ghiringhelli and
It occurs before the initiation of tumorigenesis and is driven by Fumet, 2019). However, this process can also contribute to
factors such as infections, dysregulated immune responses, and tumorigenesis and the suppression of antitumor immunity. For
environmental triggers. Environmental factors including instance, IL-1α released by necrotic cells promotes malignant
Oxidative stress, exposure to mutagenic compounds, constant transformation, angiogenesis, and metastasis. Simultaneously, it
exposure to proliferative inflammatory stimuli, and defects in activates and polarizes fibroblasts towards an inflammatory
the epithelial barrier can initiate and promote chronic phenotype, fostering tumorigenesis (Sahai et al., 2020).
inflammatory reactions. The chronic inflammatory state Conversely, ionizing radiation has been observed to increase the
induced by these factors may lead to DNA damage or population of Treg cells in skin cancer (Price et al., 2015), while
epigenetic changes, creating a favorable environment for the drugs like oxaliplatin induce the recruitment of plasmacytes
development of tumors. Two events are crucial for inducing expressing immunosuppressive markers such as IgA, IL-10, and
tumor development from normal cells: a tumorigenic event PD-L1, in a TGF-β receptor signaling-dependent manner in prostate
involving the accumulation of mutations or epigenetic cancer (Shalapour et al., 2015). It is crucial to note that therapy-
alterations, and the clonal expansion of altered cells leading to induced tumor cell death promotes the production of growth factors
tumor formation. Inflammation contributes to both events by and cytokines, including WNT, EGF, TNF, IL-17, and IL-6, by cells
inducing DNA damage, increasing oxidative stress from tissue- in the TME to promote the survival of remaining tumor cells and
resident cells, or innate immune cells recruited to the TME in the play a role in fostering therapy resistance (Greten and Grivennikov,
absence of exogenous carcinogens (Meira et al., 2008; Schmitt and 2019). The release of damage-associated molecular patterns
Greten, 2021). (DAMPs) from necrotic cells and the TME can trigger tumor-
promoting inflammation that can impact the overall dynamics of
the tumor microenvironment, influencing the course of cancer
5.2 Inflammation caused by tumor progression.
progression Understanding these distinct types of inflammation and their
temporal association with cancer pathogenesis is crucial for
This type of inflammation that supports tumor growth, is developing targeted interventions and therapeutic strategies
highly dependent on cell-cell interactions within the TME of tailored to the specific inflammatory context at different stages of
sporadic tumors, promoting local growth and metastasis cancer development.
formation (Greten and Grivennikov, 2019). This protumor
inflammatory response can be triggered by events such as
hypoxia-induced cell death, fracture of the epithelial barrier and 6 Therapeutic approaches in cancer
the subsequent entry of microbial compounds. These conditions
within the tumor microenvironment contribute to the Therapeutic strategies targeting cancer-associated inflammation
establishment of an inflammatory milieu that aids in the include the exploration of anti-inflammatory drugs, particularly
progression and survival of cancer cells. In CRC, loss of non-steroidal anti-inflammatory drugs (NSAIDs), which function
p53 function affects epithelial integrity activating NF-kB and by inhibiting COX enzymes. Epidemiological and preclinical data
STAT3 inflammatory pathways (Schwitalla et al., 2013). indicate the potential utility of these drugs in cancer prevention and
Hypoxia, nutrients deficiency in poorly vascularized tumor areas treatment (Crusz and Balkwill, 2015; Wong, 2019; Zappavigna et al.,
and necrotic cell death, lead to the secretion of proinflammatory 2020; Michels et al., 2021). As an example, aspirin, an NSAID, has
factors (Jorgensen et al., 2017; Kim et al., 2019). Hypoxia also induces demonstrated promise in reducing the risk of esophageal, liver,
hypoxia-inducible factor 1α (HIF1α) expression, activating tumor- breast, and colorectal cancer and it is associated with a reduced risk
associated fibroblasts and recruiting immune cells, including of metastasis, particularly in patients with adenocarcinomas
monocytes, macrophages, and B-cells to the TME (Ammirante (Table 3) (Algra and Rothwell, 2012; Rothwell et al., 2012).

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TABLE 3 Preventive and anticancer effects of some anti-inflammatory drugs.

Medication Effect
Aspirin Preventive effect in breast, bladder, esophagus, lung, and colorectal cancers

Dexamethasone In multiple myeloma, it induces cell death by expression of miR-125b. Preventive effect in breast cancer, multiple myeloma, and CRC

Ibuprofen It inhibits β-catenin nuclear activation in human colon adenoma

Sulindac It induces NF-κB pathway activation in colon cancer cells. Preventive effect on breast cancer

Statins Preventive effect in renal cell carcinoma, lung, prostate, and colorectal cancers

Source: Elaborated from information about (Xiao and Yang, 2008; Zappavigna et al., 2020).

TABLE 4 Example of classification of inflammatory factors and effects on cytokine levels.

Inflammation type Factor IL-1β TNF-α IL-6 IL-8 IL-12 INF-α IFN-γ
Ischemic stroke E E E

Atherosclerosis E E E

VII Infarction E E E

VI Diabetes E E E E E E

Osteoarthritis E E E E

Rheumatoid arthritis E E E E

V Colon cancer E E E E E

Lung cancer E E E E

Gastric cancer E E E E

Breast cancer E E E E

Esophageal cancer E E E E E D

Source: Adapted from (Roe, 2021b). E, Elevated; D, Decreased below normal levels.

Despite these promising findings, it is crucial to exercise caution (Michels et al., 2021), and IL-8 (Khandia and Munjal, 2020),
in the use of NSAIDs other than aspirin due to potential risks. The among others (Table 4), highlight the importance of
use of such drugs has been associated with an increased risk of establishing a classification system. Despite progress, there is
bleeding, myocardial infarction, gastrointestinal bleeding, and renal currently no consensus on the causative factors that influence
failure. These adverse effects arise from the modulation of signaling the levels of these markers in the context of cancer-associated
pathways by NSAIDs, emphasizing the need for careful evaluation inflammation (Roe, 2021a). Additional research is imperative to
when considering the use of alternative NSAIDs for cancer refine our understanding of the specificity of inflammatory
treatment and prevention. It is essential to recognize that the markers (Bhavsar et al., 2014) while there is evidence indicating
underlying mechanisms and potential side effects of these drugs a pivotal role of proinflammatory cytokines, enzymes, and
are not yet fully understood (Wong, 2019; Michels et al., 2021). transcription factors in promoting tumorigenesis, it is
Another therapeutic approach for cancer-associated important to note that the inhibition of proinflammatory
inflammation involves selectively suppressing crucial pathways may not always be beneficial (Sethi et al., 2012). For
proinflammatory mediators, using blockers specifically targeting instance, the transcription factor NF-kB, closely related to various
TNF-α (Hou et al., 2021), NF-κB (Shishodia et al., 2003; Capece cancer features (Capece et al., 2018), has been found to exert
et al., 2018), and COX-2 (Chatterjee et al., 2018). However, many inhibitory effects on tumor development (Dajee et al., 2003). This
potential inflammatory biomarkers lack cancer specificity (Eugen- duality underscores the complexity of inflammatory pathways, and
Olsen et al., 2010), necessitating a thorough assessment to ensure inhibiting them might act as a double-edged sword, influencing
their utility in patients follow-up, therapeutic response, and cancer- tumor progression in multifaceted ways. Thus, understanding the
associated inflammation monitoring. intricate interplay between inflammation and cancer is essential to
While C-reactive protein (CRP) has been suggested as a develop targeted and effective therapeutic interventions (Michels
potential inflammation biomarker, its expression levels can be et al., 2021).
influenced by several factors. Additionally, the presence of An alternative therapeutic approach to modulate chronic
multiple CRP isoforms makes it difficult to establish a direct inflammatory process involves the use of plant-derived
relationship with cancer development (Roe, 2021a). Other products, which enclose a diverse array of compounds with
markers, such as cytokines IL-6 (Masjedi et al., 2021), TNFα pleiotropic properties capable of impacting molecular pathways

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FIGURE 5
Main risk factors and inflammatory molecules associated with chronic diseases. Adapted from (Gupta et al., 2018b) with additional elements from
(Suryavanshi et al., 2021).

common to both inflammatory phenomena and cancer (Garcia such as musculoskeletal toxicity (Bramhall et al., 2001; Cathcart
et al., 2014; Cragg and Pezzuto, 2016). Regular inclusion of these et al., 2015; Chatterjee et al., 2018). The pursuit of well-defined
compounds in the diet, or their use in the treatment of established therapeutic profiles and safety considerations remains crucial for the
diseases has demonstrated potential in preventing development of effective plant-derived products in
inflammation (Figure 5). cancer treatment.
Many cancer patients incorporate plant-derived products
into their regimen during antineoplastic therapy, either to
mitigate the side effects of conventional therapy or as 7 Endocannabinoid system (ECS)
adjuvants to enhance therapeutic outcomes (Desai et al.,
2018). An illustrative example of the pleiotropic properties of The endocannabinoid system involves a complex interplay of
plant-derived products is curcumin, a derivative of Curcuma components, which include lipid endocannabinoids (ECs) such as
longa which can modulate the arachidonic acid pathway (Yarla anandamide (AEA) and 2-arachidonoylglycerol (2-AG),
et al., 2016). Curcumin negatively regulates COX-2 expression by synthesizing enzymes like NAPE-PLC and DAGL, hydrolyzing
inhibiting NF-κB (Hong et al., 2004; Garcia et al., 2014). enzymes like FAAH and MAGL, and relevant receptors like a
Furthermore, curcumin modulates the AKT/mTOR pathway cannabinoid receptor-1 (CB1R), cannabinoid receptor-1 (CB2R),
and the expression of MMP-9 (Shishodia et al., 2003), a TRPV1, PPARγ, and GPR55 (Volkow et al., 2017). This system is
member of the MMP family regulating metastasis ubiquitously distributed throughout the body, exerting diverse
development (Chatterjee et al., 2018). modulatory functions on various organs. Its notable impact on
Despite promising results obtained with curcumin in animal regulating food intake, perceiving pain, managing stress
models and humans, including encouraging effects on overall responses, influencing glucose tolerance, and controlling cell
survival in patients with pancreatic and non-small cell lung proliferation, differentiation, and metabolism highlights its
cancer, further studies are needed to clearly define its utility in potential therapeutic effect in cancer treatment (Pacher et al., 2020).
cancer treatment (Bahadori and Demiray, 2017). It is noteworthy Alterations in the endocannabinoid system have been
that several MMP inhibitors like marimastat and tanomastat initially implicated in various diseases, including neurodegenerative
showing effectiveness comparable to conventional disorders, multiple sclerosis, inflammation, and cancer (Laezza
chemotherapeutics, faced challenges in clinical trials due to lack et al., 2020). Research has underscored the potential therapeutic
of selectivity and side effects (Nelson et al., 2017; Desai et al., 2018), effects of ECs in cancer treatment, with reports indicating antitumor

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FIGURE 6
The interplay between arachidonic acid, endocannabinoids, and prostamides, along with drugs that modulate their expression, influences
inflammatory-related diseases. LT receptor, leukotrienes receptor; LOX, lipoxygenase; CBD, cannabidiol; THC, tetrahydrocannabinol; NAPE-PLD,
N-acylphosphatidylethanolamine-specific phospholipase D; PLC, phospholipase C; ABHD4, α/β-hydrolase domain-containing 4; AM404,
N-arachidonoylphenolamine; Ca2+−NAT, calcium-dependent N-acyltransferase; PLA2, phospholipase A2; PLD, phospholipase D; FAAH, fatty acid
amide hydrolase; and HETEs, hydroxyeicosatetraenoic acids.

effects in various cancer types, including breast cancer (Laezza et al., physical and emotional stressors in these conditions can induce
2006), CRC (Lee et al., 2022; Silva-Reis et al., 2023), gliomas (Salazar the release of adrenal corticosteroid hormones in both rodents and
et al., 2009; Costas-Insua and Guzmán, 2023), and others (Pisanti humans (Joëls, 2018). Elevated corticosteroids levels in serum have
et al., 2013; Pagano et al., 2023). been linked to changes in the endocannabinoid system (Wamsteeker
Research indicates that conditions such as hypoxic stress can et al., 2010). Studies such as those conducted by Sugimoto et al.
affect the endocannabinoid system, potentially increasing malignant (2019), suggest that corticosterone may counteract the beneficial
activity in cells, such as glioblastoma cells. This effect is seen through antitumor effects of ECs by reducing CB1R activity in glioblastoma
the downregulation of CB1R and the upregulation of models, thus promoting cancer growth. Given that stress is common
COX2 receptors (Sugimoto et al., 2017). Additionally, both in many diseases and corticosteroids are commonly used in treating

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TABLE 5 Cannabis-based pharmaceutical drugs approved and marketed to 2023.

Active pharmaceutical Drug Indication Reference

ingredient name
Dronabinol (synthetic THC) Marinol®/ Antiemetic associated with chemotherapy and HIV/AIDS-induced FDA (1985), Silvinato et al.
Syndros® anorexia (1992)

Cannabidiol Epidiolex® Dravet syndrome and Lennox-Gastaut Seizures associated with tuberous FDA (2017), Golub and Reddy
sclerosis complex (2021)

Nabilone (synthetic analog of THC) Cesamet® Chemotherapy-induced nausea and vomiting CESAMET Nabilone Capsules
(2022)

CBD:THC (Nabiximols 1:1 Plant-derived) Sativex® Multiple sclerosis (MS) related spasticity and Pain associated with MS Keating (2017), Health Canada
and cancer (2019)

inflammation and cancer, there is a debate about whether 4. Inhibition of cell proliferation and migration through
monitoring endocannabinoid levels could provide insights into GPR55 antagonism, leading to suppression of pathways
disease progression by regulating their activity. promoting cancer cell survival and mobility (Pellati et al., 2018).
The evidence suggests that cannabinoids are potent anti-
inflammatory agents for treating chronic inflammatory diseases, These findings suggest that cannabinoids hold potential as
although the precise mechanisms are not fully understood. Many therapeutic agents against cancer, offering multiple avenues for
chronic inflammatory conditions, including Coronavirus Disease intervention in cancer progression.
2019 (COVID-19), involve a phenomenon called the cytokine Cannabinoid medicines have gained approval from regulatory
storm, where there is an uncontrolled and severe inflammatory agencies including the United States Food and Drug Administration
response leading to the accumulation of proinflammatory cytokines (FDA), as listed in Table 5. Notably, Phyto cannabinoids like
(Suryavanshi et al., 2022). Modulating the endocannabinoid system Cannabidiol (CBD) and Tetrahydrocannabinol (Dronabinol,
using cannabis derivatives and other medications (Romano and THC) have shown significant inhibition of
Lograno, 2007; Park et al., 2016; Mallet et al., 2023), presents a NLRP3 inflammasome activation in macrophages following LPS
promising alternative for treating and mitigating such situations. + ATP stimulation. This leads to reduced levels of IL-1β. CBD also
This approach, as illustrated in Figure 6, could offer additional reduced NF-κB nuclear factor phosphorylation, while both CBD and
therapeutic benefits. THC mitigated post-LPS oxidative stress.
ELISA data reveals substantial reductions in IL-6, IL-8, and
tumor necrosis factor α (TNF-α) levels in macrophages following
8 Anti-inflammatory and anticancer LPS treatment. Additionally, both CBD and THC significantly
effects of cannabinoids reduce STAT3 phosphorylation in macrophages, attributed to
decreased phosphorylation of tyrosine kinase-2 (TYK2) after LPS
Medical cannabinoids have demonstrated effectiveness in treating stimulation (Desai et al., 2018).
a range of diseases including Inflammatory Bowel Disease (IBD) Another phytocannabinoid, tetrahydrocannabivarin (THCV)
(National Academies of Sciences, 2017), neurodegenerative disorders downregulates IL-1β, IL-6, TNFα, and COX-2 at the protein
(Golub and Reddy, 2021), cancer (Mangal et al., 2021), anorexia, and level, possibly due to its effects on various stages of gene
weight loss (Bajtel et al., 2022; Pennant and Hinton, 2023). In the expression. At concentrations of 5 μM and 15 μM, THCV
context of cancer, cannabinoids show promise as anticancer agents effectively inhibits NF-κB activation, which controls the
through several mechanisms: transcription of numerous proinflammatory proteins including
Pro-IL-1β, IL-6, Pro-TNFα, and COX-2 (Gojani et al., 2023).
1. Induction of apoptotic death in glioma (Velasco et al., 2016), Evidence suggests that CBD can suppress EGF/EGFR
hepatocellular carcinoma (Vara et al., 2011) and pancreatic signaling, and downstream targets such as NF-κB, play roles in
cancer cells (Carracedo et al., 2006), by stimulating the inflammation and cell growth regulation (Pellati et al., 2018).
synthesis of ceramide via CB1 and CB2 receptors. This Additionally, it has been demonstrated that CBD and CBG can
process involves the upregulation of stress-regulated ameliorate inflammation in animal models of IBD (Borrelli et al.,
proteins, leading to inhibition of pathways promoting 2013; Hasenoehrl et al., 2016). Given the close association between
autophagy-mediated cell death. IBD and an increased risk of CRC (Lucafò et al., 2021), recent
2. Reduction of HIF-1α expression in Glioblastoma cells, research by Jeong et al. (2019), demonstrated the CBD’s ability to
resulting in decreased cancer cell growth and proliferation inhibit the induced dose-dependent growth and apoptosis of
(Solinas et al., 2013). human CRC cells, while sparing normal colorectal cells.
3. Delayed tumor progression in human colon cancer cells by Additionally, CBD reduced tumor volume and stimulated
inhibiting HIF-1α expression and its target genes VEGF and apoptosis in a xenograft model, indicating its potential efficacy
COX-2 (Thapa et al., 2012), as well as activation of AMPK- as a reliable anticancer agent in vivo (Jeong et al., 2019).
related kinases to regulate energy metabolism in cancer cells Furthermore, a pilot study by Ng et al. (2023) involving three
(Dando et al., 2013). CRC patients, revealed that THC could alleviate CRC cachexia

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associated with inflammation and immune responses. After THC associated with senescence and the inflammatory phenomena
treatment, a decrease was observed in the level of six cytokines in linked to carcinogenesis can inform targeted interventions. The
serum samples, including IL-6 and TNF-α, as well as chemokine use of natural products and their derivatives emerges as a
(C-C motif) ligand 2 (CCL2), known for its unfavorable effects on promising therapeutic alternative or as an adjuvant for cancer-
tumor prognosis (Jin et al., 2021), and reviewed elsewhere (Xu related inflammation, often presenting a more favorable adverse
et al., 2021). These findings collectively underscore the promising effect profile than conventional therapeutic agents (Deng et al., 2017;
therapeutic potential of cannabinoids in addressing inflammation Desai et al., 2018; Deng et al., 2020). However, the development of
and combating CRC progression. drugs based on bioactive natural products poses challenges due to
Cannabichromene (CBC) interacts with CB1 and their inherent variability, complexity and the need for
CB2 receptors, influences cellular endocannabinoid reuptake standardization and rigorous research processes (Desai et al.,
and acts as an agonist on TRPA1 and adenosine receptors. 2018; Huang et al., 2021).
These actions lead to downstream effects such as suppression In addition, anti-inflammatory products, including NSAIDs
of MAGL function, decreased intracellular nitric oxide (NO) and (Zappavigna et al., 2020), corticosteroids (Wang et al., 2004),
IFNγ levels in macrophages, and modulation of cytokine and and statins, (Masjedi et al., 2021), along with plant-derived
COX-2 gene transcription. The precise mechanisms underlying products hold clinical utility as adjuvants to traditional
CBC’s anti-inflammatory properties involve both CB1R and therapies. Their potential accessibility and known safety
CB2R mediated signaling as well as TRPA1 agonism (Udoh profiles, make them an attractive alternative for the general
et al., 2019), which helps mitigate inflammatory responses population. Combining anti-inflammatory drugs with
associated with cytokine and COX-2 transcriptional adjustments in dosage and dosing regimens could represent a
modulation (Gojani et al., 2023). On the other hand, novel strategy in antitumor therapy (Binnewies et al., 2018;
Cannabinol (CBN) modulates NFκB activation primarily by Zappavigna et al., 2020).
regulating phosphorylation rather than transcription. It has a Moreover, the exploration of endocannabinoid, cannabinoid,
dose-dependent effect on P-NFκB levels, with lower doses and prostamide-type compounds as potential therapeutic targets or
yielding more pronounced effects. While CBN upregulated the biomarkers of inflammatory and immune processes in tumor
transcription of COX-2 and Pro-TNFα genes, it simultaneously development requires further investigation to elucidate their
decreases their protein levels, suggesting a potential post- pharmacology and significance before transitioning to clinical
transcriptional mode of action. Additionally, CBN exhibited practice. Recent evidence suggests that cannabinoids may inhibit
inhibitory effects on IL-1β and IL-6 gene transcription, likely tumor cell proliferation and serve as supportive therapy for anti-
mediated by negative regulation of NF-κB phosphorylation and tumor treatments due to their multiple therapeutic targets
activation (Gojani et al., 2023). contributing to anti-neoplastic effects. Ongoing clinical studies
Overall, both CBC and CBN demonstrated diverse anti- with nabiximols (Sativex) indicate promising potential in the
inflammatory properties through distinct mechanisms. CBCs treatment of glioblastoma. The first, known as ARISTOCRAT
effect appear to involve modulation of cannabinoid reuptake (NCT05629702), is a phase II, multi-center, double-blind,
TRPA-1 agonism and CB receptor signaling, while CBN placebo-controlled, randomized trial aimed at comparing the
primarily exerts its effects through regulation of NFκB cannabinoid Nabiximols with a placebo in patients with
phosphorylation and potential post-transcriptional mechanisms recurrent MGMT methylated glioblastoma (GBM) treated with
(Gojani et al., 2023). These findings support the potential use of temozolomide (TMZ). The second study (NCT03529448) is a
cannabinoids as anti-inflammatory agents for various chronic Phase Ib, open-label, multicenter, intrapatient dose-escalation
inflammatory diseases and provide insights into their clinical trial designed to assess the safety profile of the (THC:
mechanisms of action. CBD 1:1) combination with temozolomide and radiotherapy in
patients newly diagnosed with glioblastoma.
Understanding factors like genetic variability, environmental
9 Analysis and conclusion exposure history, dietary habits, microbiome composition, and
cellular plasticity within the TME, promises insights into the
This extensive review highlights the urgent need for further intricate interrelationships governing carcinogenic phenomena
research to discover valuable biomarkers for cancer diagnosis, and may contribute to the discovery of diagnostic or clinically
prevention, and treatment. The relationship between obesity, relevant biomarkers (Greten and Grivennikov, 2019; Martin
chronic inflammation, and cancer emphasizes the importance of et al., 2021), establishing possible therapies based on molecular
population-based interventions, including the maintenance of and genetic analysis in patients.
healthy body weight as a preventive measure (Kolb et al., 2016; In conclusion, a Poly pharmacological approach to modulate the
Lauby-Secretan et al., 2016). Moreover, the association between the complex signaling of inflammation and cancer appears to be the
dietary inflammatory index and increased cancer risk suggest the most promising option. Given the systemic and multifactorial
potential effectiveness of an anti-inflammatory diet supplemented nature of inflammation (Hou et al., 2021), targeting multiple
with nutraceuticals (Jayedi et al., 2018) and coupled with a healthy proteins involved in inflammation and cancer pathogenesis is
lifestyle for cancer prevention (Michels et al., 2021). deemed more effective than focusing on a single gene, protein, or
Furthermore, the characteristics of senescence and the impact of signaling pathway. While short-term treatments may benefit from
SASP on TME provide opportunities for developing improved targeting a single therapeutic target, a comprehensive strategy that
therapeutic strategies. Understanding the vulnerabilities addresses the persistent nature of inflammation and the involvement

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of multiple signaling pathways in cancer cells is crucial for long- was funded by Instituto Nacional de Cancerología Grant Number
term success. XRPM: C19010300-454, (to JR).

Author contributions Conflict of interest

AT-S: Conceptualization, Investigation, Methodology, The authors declare that the research was conducted in the
Writing–original draft. SC-H: Conceptualization, Resources, absence of any commercial or financial relationships that could be
Writing–review and editing. LM-G: Conceptualization, Project construed as a potential conflict of interest.
administration, Writing–review and editing. PM-C:
Conceptualization, Writing–review and editing. JR-G:
Conceptualization, Funding acquisition, Investigation, Publisher’s note
Supervision, Validation, Writing–review and editing.
All claims expressed in this article are solely those of the authors
and do not necessarily represent those of their affiliated
Funding organizations, or those of the publisher, the editors and the
reviewers. Any product that may be evaluated in this article, or
The author(s) declare that financial support was received for the claim that may be made by its manufacturer, is not guaranteed or
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