Nomenclature

Oncology: is the study of tumors and neoplasms

Neoplasia: refers to new growth
Neoplasm: it is defined as a genetic disorder of cell growth that is triggered by an acquired or (less commonly)
inherited mutation affecting a single cell and its colonial progeny. It refers to the collection of cells and stroma which
comprise new growth
 These mutations give the neoplastic cells with a survival/growth advantage that result in excessive proliferation
that is independent of growth and control signals
 When a neoplasm (benign or malignant) produces a grossly visible projections above mucosal surface such as in
gastric or colon lumen it is termed as polyp
 Majority of tumors (including mixed tumors) are composed of cells from a single germ layer

Tumors: are composed of parenchyma (neoplastic cells) and reactive stroma (connective tissue, blood vessels and
cells of immune system)
 Biological behavior and classification of tumors is based on the parenchymal component
 Growth and spread of tumor are dependent on stroma. Some tumors have scanty connective tissue and the
neoplasm is soft and fleshy. In other tumors parenchymal cells stimulate formation of abundant stroma
(desmoplasia). Desmoplastic tumors such as in female breast cancer are stony hard (scirrhous)
Benign tumors: remain localized at their site of origin and amenable to surgical removal.
 In most cases patient survives except when they arise in vulnerable locations such the brain where they may cause
significant morbidity and are sometimes fatal
Naming of benign tumors
 Benign tumors of mesenchymal origin end with “oma” I-e tumor of fibroblast like cell (fibroma),
cartilaginous tumor (chondroma)
 Benign neoplasm derived from glandular epithelia are referred to as adenoma even if they fail to form
glandular structures
 Benign epithelial neoplasms forming finger-like/ warty projections from epithelial surfaces are called
papilloma
 Benign epithelial neoplasms forming large cystic masses are called cystadenomas
 Tumors producing papillary projections that protrude in cystic spaces are called papillary cystadenomas
 If a poly has glandular tissue it is called adenomatous polyp
 Hamartomas are disorganized masses composed of cells indigenous to the involved tissue. Most of them have
clonal chromosomal aberrations that are acquired through somatic mutations
Malignant tumors: can invade and destroy adjacent tissues and spread to distant sites (Metastasize)
 They are collectively referred to as cancers
 Not all cancers purse a deadly course some are discovered at early stages and are surgically excised while others
are treated with systematically administered drugs/ therapeutic antibodies
Naming of malignant tumors
 Malignant tumors arising in solid mesenchymal tissues are usually called “sarcomas” (e.g., fibrosarcoma,
chondrosarcoma)
 Malignant tumors arising from blood forming cells are designated leukemias
 Malignant tumors of lymphocytes or their precursors are called lymphomas
 Malignant neoplasms of epithelial cell origin are called carcinomas.
 Tumor cells resembling stratified squamous epithelium are called squamous cell carcinoma.
 Neoplastic epithelial cells arranged in glandular pattern are called adenocarcinomas
 In approximately 2% of cases cancers are composed of cells of unknown origin and are designated as
undifferentiated malignant tumors
Mixed tumors: all parenchymal cells don’t resemble each other and more than one line of differentiation is evident
creating different sub populations of neoplastic cells
 Tumor arising from a single neoplastic clone capable of forming both mesenchymal and epithelial cells is called
pleomorphic adenoma
 Classic example is the mixed tumor of salivary gland which contains epithelial components in myxoid stroma that
may contain islands of cartilage or bone.
 Tumor containing recognizable mature or immature cells from more than one germ layer (sometimes all three) are
referred to as teratomas. They originate from totipotent stem cells present in ovaries, testes and sometimes in
abnormal midline embryonic rests
 A common example is ovarian cystic teratoma (dermoid cyst) that differentiated principally along ectodermal
lines to create a cystic tumor lined with squamous epithelium that is filled with hair, sebaceous glands and tooth
structures
Choristoma: heterotrophic (misplaced) rests of cells. For example a small nodule of well developed normally
organized pancreatic tissue may be found in the submucosa of the stomach or small intestine.

Differentiation: refers to the extent to which neoplastic parenchymal cells resemble the corresponding normal
parenchymal cell in terms of morphology and functionality
Anaplasia: lack of differentiation
Pleiomorphism: refers to variations in cell size and shape
Metastasis: is the spread of a tumor to sites that are physically discontinuous with the primary tumor

Well-differentiated tumors
 Benign and malignant tumors have a greater likelihood of retaining the functional capabilities of their normal
counterparts.
 In some cases, such as in tumors of endocrine gland the cells continue to produce and secrete hormones which can
be detected and quantified as a means to diagnose and follow the response of tumors to treatment.
 Examples include well differentiated hepatocellular cancer that expel bile and well differentiated squamous cell
carcinomas that synthesis keratin
Anaplastic tumors
 They typically lose the specialized functional activities of their cell of origin
 They sometimes acquire new and unanticipated functions
 For example, bronchogenic carcinomas may produce corticotropin, insulin, glucagon, and other hormone giving
rise to paraneoplastic syndromes
 Comparison between benign and malignant tumors
Characteristics Benign Malignant
Rate of growth Generally slower than malignant Tends to grow more rapidly (growth rates vary in
tumors (may come to a standstill different malignant tumors)
or regress)
Differentiation Generally, well differentiated May be well differentiated, moderately well
differentiated or anaplastic
Mitosis/ Mitosis is rare and mitotic figures Mitosis is common and atypical mitotic figures are
mitotic figures are normal seen
Ranges from small undifferentiated cells to tumor
Pleomorphism Generally, absent but may occur giant cells (some have a single large polymorphic
to a mild degree nucleus while other possess two or more large
hyperchromatic nuclei)
Disproportionately large nuclei (nuclear-to-cytoplasm
ratio may approach 1:1 instead of the normal 1:4 to
Nuclear Generally, normal but may be 1:6). Shape of nucleus is often irregular. Chromatin is
morphology slightly abnormal often clumped and distributer long the nuclear
membrane or is hyperchromatic
Generally, absent but some may Orientation of cells with respect to each other or
Loss of exhibit mild to moderate degrees other supporting structures like basement membrane
polarity of loss of polarity (particularly in is markedly disturbed (sheets/masses of tumor cells
cases where the tumor is growing grow in a disorganized fashion)
rapidly or in an abnormal
location)
Metastasis Remain localized to site of origin Frequent
Highly invasive (don’t recognize normal anatomical
Invasiveness Non invasive boundaries) which makes complete surgical resection
difficult or impossible
Encapsulated (expanding tumor Pseudoencapsulated with rows of tumor cells
Capsule applies pressure causing hypoxic penetrating the margin and infiltrating adjacent
damage which activates tissues
fibroblasts which leads to
deposition of ECM)
Miscellaneous Well demarcated, discrete and Poorly demarcated and lack well defined cleavage
readily palpable planes

Metaplasia: is the replacement of one cell type with another. It can be reversed in inciting cause is removed
 It is associated with tissue damage, repair and regeneration.
 It is an adaptation to chronic injury and the metaplastic tissue is more suitable to the new environment
 Metaplasia can make a tissue more prone to malignant transformation.
 For example, squamous metaplasia of respiratory epithelium in chronic smokers is often a prelude to the
development of cancer.
Dysplasia: is disorder growth
 Occurs principally in epithelial cells.
 Dysplastic cells exhibit considerable pleomorphism and often contain large hyperchromatic nuclei with high
nuclear to cytoplasmic ratio
 Dysplastic epithelial surfaces show architectural disarray and loss of differentiation. Example: normal
progression of tall basal cells to surface squames may fail partly or completely leading to replacement of
epithelium with all basal like cells with hyperchromatic nuclei.
 Mitotic figures are more abundant and may be seen in all the layers
 Dysplastic changes are often found adjacent to the foci of invasive carcinomas or in some cases (severe
epithelial dysplasia in cervix) antedates cancer
 Some mutations associated with full-blown cancer may be present in mild dysplasias
 Although dysplasia may be precursor to malignant transformation it does not always progress to cancer
 Removal of inciting causes may reverse the dysplastic changes even in moderately severe dysplasia
Carcinoma in situ: when dysplasia is severe and involves full thickness of the epithelium but the lesion does not
penetrate the basement membrane
 It is seen in skin, breast, bladder and uterine cervix
 They display all the cytologic features of malignancy
 Unless treated, they have a high probability of progression to invasive cancers
 Carcinoma in situ in cervix frequently antedates cancer
 Carcinoma in situ may persist for years before it becomes invasive.
 Time interval for evolution of full-blown cancers from in situ lesions relates most likely to the time required
for accumulation of all the mutations needed to induce a fully malignant phenotype

Liquid tumors: tumor derived from cells that have the capacity to enter the blood stream and travel to distant sites.
They include leukemias and lymphomas
Solid tumors: tumors derived from cells that don’t normally circulate in the blood
Metastasis in malignant tumors
 All of them can metastasize but some do so very infrequently. Examples include gliomas (malignant neoplasm
of glial cells in CNS) and basal cell carcinomas both of which invade early in their course but rarely
metastasize
 Blood cancers (leukemia and lymphoma) are always taken to be malignant as their cells of origin have the
capacity to enter the blood stream and travel to distant sites and are therefore referred to as liquid cancers
 Overall, approximately 30% of solid tumors (excluding skin cancers other than melanomas) present as a
metastatic disease
 In general, the likelihood of metastasis of a solid tumor correlate with other feature of malignancy including
differentiation, invasiveness, growth and size however there are still exceptions

Pathways of spread
Direct seeding of body cavities or surfaces
 It occurs when a malignant neoplasm penetrates into a natura “open field” lacking physical barriers
 Most often the peritoneal cavity is involved but any body cavity (pleural, pericardial, subarachnoid and joint
spaces) ay be affected
 Seeding of carcinomas arising in the ovary (which spread to peritoneal cavity) produce a heavy cancerous
coating while the cancer cells themselves remain attached to abdominal viscera
 Sometimes mucous secreting carcinomas or ovarian carcinomas produce a gelatinous neoplastic mass referred
to as pseudomyxoma peritonei

Lymphatic spread
 Most common pathway for initial dissemination of carcinomas and sometimes for sarcomas
 Tumors do not contain functional lymphatic vessels but lymph vessels located at the margins of invading
cancers are sufficient for lymphatic spread
 The pattern of spread follows the natural routes of lymphatic drainage.
 Local lymph node however may be by-passed (skip metastasis) possibly because microscopic metastasis is
missed or due to abnormal variation in normal pattern of lymph drainage
 Example include carcinomas of the breast which usually arise in the upper outer quadrants and generally
disseminate first to the auxiliary lymph nodes and then to infraclavicular and supraclavicular lymph nodes
 In breast cancer auxiliary lymph node examination is carried out to determine the prognosis and treatment
options. To avoid complete auxiliary lymph node resection and its associated morbidity biopsy of sentient
nodes is used to assess the presence or absence of metastatic lesions. Sentient node mapping can be done by
injection of radiolabeled traces/ colored dyes.
 In most cases regional nodes serve as an effective barrier against further dissemination of tumor (at least of a
while). Tumor specific immune response may lead enlargement (hyperplasia) of the lymph node. However,
enlarged lymph nodes do not always harbor metastases which can only be done by microscopic examination.
Hematogenous spread
 It is typical pathway of spread for sarcomas but is also seen with carcinomas
 Histologic evidence of penetration of small vessels at the site of primary neoplasm is an ominous feature of
metastasis. The involved blood vessels are usually small veins and arteries and larger vessels are more
resistant to penetration
 Arterial spread may however occur when tumor cells pass through pulmonary capillaries or pulmonary
atrioventricular shunts or when cancer in the lung give rise to tumor emboli.
 Blood borne tumor cells often come to rest in the first capillary bed they encounter which is why the most
frequency involved organ of hematogenous spread are the liver and lungs
 Cancer arising in close proximity to vertebral column (carcinomas of thyroid and prostate) often metastasize
through paravertebral plexus
 However venous drainage and patterns of metastatic spread do not always correlate and are mostly cancer
specific
 Examples include, Renal cell carcinoma often invades branches of the renal vein and then the renal vein to the
inferior vena cava and then to the right side of the heart. Hepatocellular cancers often penetrate portal and
hepatic radicles and then grow in the main venous channels. Remarkably such intravenous growth may
sometimes not be associated with widespread metastasis
Sentient lymph node: it is the first lymph node in regional lymphatic basin that receives flow from the primary tumor

Epidemiology of Cancer
Epidemiology: the branch of medicine which deals with the incidence, distribution, and possible control of diseases
and other factors relating to health
  In 2018 it was estimated that over 9.5 million deaths were caused by cancer worldwide representing nearly 1
in 6 deaths
 Due to increasing population size, age and cancer cases are projected to increase to 21.4 million with cancer
related deaths increasing to 13.2 million by the year 2030
 Most longitudinal data pertaining to cancer incidence comes from higher income countries where age adjusted
death rate (deaths per 100,000 population) in the last 50 years of the 20th century has increased significantly in
both men and women. However, since 1995 cancer incidence rate in men has been stable and cancer death
rate has decreased by 20%. Similarly, incidence cancer rate in women has also stabilized since 1995 and
cancer death rate has decreased by 10% since 1991.
 Decreased use of tobacco products, improved detection and treatment are responsible for decreased death rates
for lung, colorectal, female breast and prostate cancer. Sharp decline in death from cervical cancer in US is
largely attributed to “Pap smear test”

Environmental factors affecting cancer risk

About 15% of cancers worldwide are caused by infectious agents (HPV causes cervical carcinomas) with the
incidence in developing countries being roughly three times greater than in developed countries
 Cigarette smoking is implicated in cancer of the mouth, pharynx, larynx, esophagus, pancreas, bladder and
most significantly in about 90% of lung cancers
 Alcohol abuse increase the risk of carcinomas of the oropharynx (excluding lip), larynx, esophagus and liver
(by development of alcoholic cirrhosis). The risk of cancers in upper airways and digestive tracts is amplified
when combined with tobacco use
 Although the precise dietary factors that affect the risk of cancer remain a matter of debate wide geographic
variations in the incidence of colorectal, prostate, breast carcinomas have been ascribed to differences in diet
 Higher incidence of cancer is reported among obese individuals
 Lifelong cumulative exposure to estrogen stimulation (particularly if unopposed by progesterone) increase the
risk of cancers in tissues (breast, endometrium) responsive to these hormones. It is likely that some of
geographic variation in breast cancer is attributed to cultural norms that influence the timing and number of
pregnancies that a woman has in her lifetime.
 Environment carcinogens in the workplace (asbestos), food (high fat diet) and personal practices (drinking
well water containing arsenic) influence the risk of different cancers
Influence of age on the risk of cancer
 Most cancers occur in adults older than 55 years a decline in cancer rates after age 80 is due to lower number
of individuals reaching this age.
 This increased risk with age is can most likely be explained by the accumulation of somatic mutations that
accompanies aging. A decline in immune competence may also be a factor.
 In the US 10% of deaths in children younger than 15 is caused by cancer. However, the types of cancers that
predominate children are different from adults partly because the pediatric cancers are more likely to be
caused by inherited mutations (particularly in tumor suppressor genes) than environmental carcinogens
 Acute leukemia and distinctive neoplasms of CNS cause approximately 60% of childhood cancer deaths. The
common neoplasms of infancy and childhood include small blue cell tumors such as neuroblastoma, Wilms
tumor, retinoblastoma, acute lymphoblastic leukemia and rhabdomyosarcoma.

Acquired predisposing conditions to cancer

 Chronic inflammatory conditions and precursor lesions are all associated with increased rates of cellular
replication such proliferating cells are at higher risk of somatic mutations required for neoplastic
transformation
 Immunodeficiency states predispose to virus-induced cancer

Chronic inflammation
 Tumors arising in context of chronic inflammation are mostly carcinomas, but also include mesothelioma and
several kinds of lymphomas
 As with any tissue injury, chronic inflammation is accompanied by compensatory proliferation of cells that
serves to repair the damage. However, in some cases, chronic inflammation may increase the pool od tissue
stem cells which may be particularly susceptible to neoplastic transformation.
 Activated immune cells produce reactive oxygen species damage DNA and inflammatory mediators that
promote cell survival
 Practical implication of the link between cancer chronic inflammation: the diagnosis and effective treatment
of H. Pylori gastritis which resolves the chronic condition that might have led to gastric cancer
Precursor lesions: localized morphologic changes that identify a field of epithelium that is at increased risk for
malignant transformation
 These changes may take place as hyperplasia, metaplasia or dysplasia. Precursor lesions consisting of
hyperplasia often stem from chronic exposure to trophic factors
 One of the most common precursors of this type are endometrial hyperplasia caused by estrogen stimulation
 Other “at risk” lesions consist of benign neoplasms an example of which is colonic villous adenoma which
progresses to cancer in about 50% of the cases if left untreated. However most benign tumors rarely transform
(pleomorphic adenoma, uterine leiomyomas) and other not at all (lipomas)

Immunodeficiency
 Immunodeficient patient (especially those with defects in T-cell immunity) are at increased risk of cancer
especially types caused by oncogenic viruses presumably because these individuals have a higher-than-normal
incidence of chronic infection with viruses
 Virus associated tumors include lymphomas, certain carcinomas and some sarcoma and sarcoma-like-
proliferation

Genetic predisposition and interactions between environmental and inherited factors

 In some families, cancer is an inherited trait, usually due to germline mutations in tumor suppressor genes
 While evidence suggests the cancers are largely attributable to environmental factors or acquired predisposing
conditions, lack of family history does not preclude an inherited component
 It is generally difficult to sort out hereditary and non-hereditary contribution due to their complex interactions
(especially when tumor development depends on the action of multiple genes)
 Even in cancers with a well-defined inherited component, the risk of cancer development may be greatly
influenced by non-genetic factors
 An example of environmental factors: breast cancer risk in female who inherit copies of BRCA1 or BRCA2
(tumor suppressor genes) have been observed to be almost threefold higher in female born after 1940 (may be
due to changes in reproductive history)
 Conversely genetic factors alter the likelihood of cancer (primarily induced by environmental carcinogens)
such as genetic variation (polymorphism) in certain enzymes such as P-450 system (influences conversion of
procarcinogen to active carcinogens). Polymorphism in one of the p-450 genes confers susceptibility to
smoking-induced lung cancer

Molecular basis of cancer

Carcinogenesis/tumorigenesis: conversion of normal cells to tumor/cancer cells for the development of cancer/tumor
Driver mutations: mutation that contribute to the acquisition of cancer hallmarks
Passenger mutations: mutations that have no phenotypic consequence
Tumor progression: pernicious tendency of a tumor to become more aggressive over time
Role of genetic and epigenetic alterations
 Non-lethal genetic damage is the first step required for the development of cancer. The initial mutation may
be acquired, inherited or may be spontaneous/random
 A tumor is formed by colonial expansion of a single precursor cell that has incurred genetic damage. Thus, all
the tumor cells will have the same set of mutations that were present at the time of neoplastic transformation
 Proto-oncogenes, tumor suppressor genes, genes that regulate apoptosis and genes involved in DNA repair are
the principal targets of carcinogens
 Mutations that activate proto-oncogenes may either cause the appearance of new function that it
oncogenic or cause an increase in the normal function(s) of the encoded gene products that promote
tumorigenesis. Because these mutations cause “gain of function” neoplastic transformation can take place
even if a normal allele is present
 Mutations that affect tumor suppressor genes cause a “loss of function” and in most cases both the alleles
must be damaged before transformation can take place. However, in some circumstances loss of one allele
(haploinsufficiency) might be enough to reduce the encoded gene product enough to allow cell
proliferation and survival
 Abnormalities in genes regulating apoptosis include gain-of-function mutations in genes whose products
suppress apoptosis and loss-of-function mutations in genes whose products promote cell death
 Loss of function mutations in genes that repair DNA damage results in the affected cell acquiring
mutations at an accelerated rate. Such a state is called mutator phenotype and is marked by genomic
instability
 Since no single mutation is fully transforming, after the imitating mutation, an number of driver mutations are
required for the development of cancer. The time required for these mutations is unknown in most cancers but
appears to be lengthy even in aggressive cancers such as acute lymphoblastic leukemia where initiating
mutations can be found in blood samples decades before diagnosis
 The persistence of initiating cells during this preclinical prodrome supports the idea that cancer arises from
cancer stem cells (cancer cells with stem cell like properties)
 Loss of function mutations in genes that repair cell damage is an early step of malignancy (particularly in
solid tumors). It increases the frequency of driver mutations as well as passenger mutations (to a greater
extent). As result during the time the cell acquires all the driver mutation hundreds or thousands of passenger
mutations may have all occurred
 Mutations in many other genes contribute to tumorigenesis by interfering in host immune responses or by
altering interactions with stroma or by other mechanisms. These are not driver or passenger mutations.
 Epigenetic aberrations also contribute to the malignant properties of cancer. These modifications include
DNA methylation (tends to silence gene expression), modification of histones (may either enhance/dampen
gene expression)
 These modifications can be passed on to daughter cells but on occasions alterations may occur
 The epigenetic state of cell determines the linage commitment and differentiation state of both normal and
neoplastic cells
 Unlike genetic modifications these are potentially reversable by drugs that inhibit DNA modifying or histone
modifying factors

Tumor evolution
 Tumors evolve genetically during their outgrowth and progression under pressure of Darwinian selection
 Early on, all the cells in a tumor are identical
 By the time the tumor comes to clinical attention (generally when it attains a mass of 1gm or 10 9 cells) it has
gone through a minimum of 30 cell doublings (it is an underestimation as a fraction all tumor cells die by
apoptosis)
 During the expansion process tumor cells acquire additional mutations and as a result the constituent cells are
often extremely heterogenous
  Cause of tumor progression: these tumor subclones compete for access to nutrients and microenvironmental
niches and those who are most fit dominate the tumor mass
 One of the most profound selective pressures is effective therapy given by physicians as tumors that recur
after therapy are almost always resistant if the same treatment is given again

Cellular and molecular hallmarks of cancer

 All cancers display eight fundamental changes in cell physiology consisting of
 Self-sufficiency in growth signals (capability to proliferate without external stimuli usually as a
consequence of oncogene activation)
 Insensitivity to growth inhibitory signals (usually due to inactivation of tumor suppressor genes that
encode components of growth inhibitory pathways)
 Warburg effect: Tumor cells undergo a metabolic switch to aerobic glycolysis (enables synthesis of
macromolecules and organelles required for cell growth)
 Evasion of apoptosis
 Limitless replicative potential (a stem cell like property that permits tumor cells to avoid cellular
senescence and mitotic catastrophe)
 Sustained angiogenesis
 Ability to invade and metastasize (property that arises due to the interplay of processes specific to tumor
and the signals that are initiated by the tissue environment)
 Ability to evade the hosts innate and adaptive immune system

Self-sufficiency in growth signals

 Oncogenes are mutated genes that cause excessive cell growth, even in the absence of growth factors and
growth-promoting external clues
 They are a mutated or overexpressed version of proto-oncogenes
 Through a variety of mechanisms these mutations increase or alter the function oncoproteins allowing them
to be constitutively active and resistant to control by external signals resulting in excessive cell proliferation
 Physiologic growth factor-induced signaling can be resolved in the following steps
 Binding of growth factor to its specific receptor
 Transient and limited activated of growth factor receptor (which in turn activate several cytoplasmic
signal-transducing proteins)
 Transmission of transduced signal to the nucleus via additional cytoplasmic effector proteins and second
messengers or by a cascade of signals transduction molecules
 Induction and activation of transcription factors and epigenetic alterations that initiate and sustain DNA
transcription
 Expression of genes that and encoded factor that promote entry and progression of the cell into the cell
cycle ultimately into cell division
 In parallel, changes in the expression of other genes that support cell survival and metabolic alteration that
are needed for optimal growth
 Aberrations in multiple signaling pathways have been identified in neoplasms and many components of these
pathways act as oncoproteins when mutated
 Conversely many tumor suppressors act by inhibiting one or more components of the same pro-growth
pathways

Oncoproteins and cell growth

 Oncogenes have multiple roles but virtually all encode oncoproteins
 In most instances, oncogenes encode oncoproteins that serve similar functions to their normal counterparts
however these oncoproteins are constitutively active and independent of growth factors)
Growth factors
 Most growth factors are made by one cell type and act on a neighboring cell of a different type expressing the
appropriate growth factor receptor
 Some cancer cells synthesize the same growth factor to which they are responsive, creating an autocrine loop
 Examples include, gliomas which expresses both PDGF and PDGF receptor and many sarcomas overexpress
TGF- α and its receptor
Growth factor receptors
 Among the large number of growth factor receptors encoded by oncogenes, the most important in cancer is
receptor tyrosine kinase
 Normally the receptor is activated transiently by binding of a specific growth factor which results in a rapid
change in receptor conformation to an active dimeric state. The activated receptor then autophosphorylates
tyrosine residues in its over intracellular tail and these modified residues serve as attachment sites for other
signaling molecules including RAS and PI3K
 The oncogenic version of these receptors results in constitutive, growth factor independent tyrosine kinase
activity.
 These changes can occur through multiple mechanisms including, point mutations, gene rearrangement and
gene amplification, example of which include:
 ERBB1 encodes for EGFR. Several different ERBB1 point mutations have been found in a subset of lung
adenocarcinomas produce constitutive activation of EGFR tyrosine kinase
 ERBB2 encodes HER2 (a different member of receptor tyrosine kinase family). It is amplified in certain
breast carcinomas leading to overexpression of HER2 receptor and constitutive tyrosine kinase activity
 ALK (receptor tyrosine kinase) may be produced in a constitutively active from as a result of gene
arrangement in a subset of lung adenocarcinomas. A deletion on chromosome 5 fuses part of the ALK
gene with EML4. The resulting EML4-ALK fusion gene encodes a chimeric EML4-ALK protein.
Downstream components of Receptor Tyrosine Kinase Signaling Pathway
 Receptor tyrosine kinase activation stimulates RAS and two major downstream signaling pathways: the
MAPK cascade and PI3K/ AKT pathway.
 When RAS mutations are present, mutations in receptor tyrosine kinases are almost always absent (at least
within the dominant tumor clone)
 Point mutations of RAS family genes constitute the most type of abnormality (approximately 15-20% of all
human tumors) involving proto-oncogenes in human tumors. However, the frequency varies among different
tumor types
 Normally activated RAS is inactivated by binding of GAPs (GTPase activating protein) which accelerates its
intrinsic GTPase activity which hydrolysis GTP to GDP
 Several distinct point mutations have been found in cancer cells that markedly reduce the GTPase activity of
RAS. As a result the RAS is always activated and cell receives pro-growth signals continuously
 The loss- of-function mutation in GAPs mimic the effect of gain-of-function mutation of RAS
 Example: disabling mutation of neurofibromin 1 (GAP encoded by NF1 gene) is associated with familial
neurofibromatosis type 1
 The MAPK and PI3K/AKT cascades both lie downstream of RAS and consist of a series of kinases many of
which are mutated in cancer cells
 Mutations in BRAF (a member of RAF family of serine/threonine protein kinases) are found in 100% of
hairy cell leukemia, 60% in melanomas and less so in colon carcinomas. Activating mutations in BRAF
stimulate downstream kinases that ultimately activate transcription factors
 Mutations in other MAPK family members downstream of BRAF are less common suggesting mutations
affecting factors near the top of the cascade are most effective
 Mutations in kinases of PI3K family are also common; 30% of breast carcinomas have PI3K gain-of-
function mutations. In other instances, such as endometrial carcinoma PI3K remains activated by loss-of-
function mutation in PTEN (negative regulator/tumor suppressor)
 Like BRAF, PI3K activates a cascade of serene/threonine kinases including AKT. KT phosphorylates
more than 150 protein and constitutes a major signaling node. Its substrates include key regulars of
protein synthesis (mTOR) and apoptosis (BAD, FOXO, MDM2, IAP and transcription factors)
Non-receptor tyrosine kinases
 Oncogenic mutations also occur in non-receptor tyrosine kinases that are normally present in the cytoplasm or
nucleus
 In many instances these mutations arise from chromosomal translocations/ rearrangements that create fusion
genes that encode constitutively active tyrosine kinases
 These non-receptor tyrosine kinases activate the same pathways as receptor tyrosine kinases
 Example: in chronic myeloid leukemia (CML) and a subset of acute lymphoblastic leukemia, the ABL gene is
translocated from chromosome 9 to chromosome 22 where it fuses with BCR gene. The resultant fusion gene
 encodes a chimeric BCR-ABL protein with constitutive tyrosine kinase activity. The most important
contribution of BCR moiety is self-association of BCR-ABL
 In other instances non-receptor tyrosine kinases are activate by point mutations that abrogate the functions of
negative autoregulatory domains, normally holding enzyme activity in check
 Example: point mutation in non-receptor tyrosine kinase JAK2 relives the tumor cell dependence on external
stimuli. Normally JAK2 participate is JAK/STAT signaling pathways which transduce mitogenic signals from
growth factor and cytokine receptors that lack tyrosine kinase activity. JAK/STAT activation alters the
expression of target genes that bind to STAT transcription factors.
Transcription Factors
 Growth autonomy may occur due to mutations affecting transcription factors that regulate the expression of
pro-growth genes and cyclins
 Transcription factors of this class include products of MYC, MYB, JUN, FOS and REL proto-oncogenes with
MYC being the most commonly affected in cancer
 MYC proto-oncogenes are expressed in all eukaryotic cells. They are rapidly and transiently induced by
RAS/MAPK signaling following growth factor stimulation
 How MYC promotes normal and neoplastic growth is not completely understood but studies have shown that
it has remarkably broad activities, several of which not only contribute to deregulated cell growth but also
several other hallmarks of cancer
 MYC activates expression of many genes that are involved in cell growth
 Some MYC target genes like D cyclins are directly involved in cell cycle progression
 It also upregulates expression of rRNA genes and rRNA processing (enhancing the assembly of
ribosomes needed for protein synthesis)
 MYC upregulates a program of gene expression that leads to metabolic reprogramming and Walburg
effect.
 MYC is considered master transcriptional regulator of cell growth. Fastest growing human tumors
(Burkitt lymphoma) virtually always have a chromosomal translocation (from chromosome 8 to
chromosome 14)
 MYC upregulates expression of telomerase contributing to the endless replicative potential of cancer cells
 MYC is one of the few transcription factors that can reprogram somatic cell into pluripotent stem cells
 In cancer cells, MYC is dysregulated through a variety of mechanisms
 In Burkitt’s lymphoma and a subset of other B- and T-cell tumors, the MYC gene is translocated (from
chromosome 8 to chromosome 14) into an antigen receptor gene containing enhancers that are highly
active in lymphocytes. Rather than driving expression of B- or T-cell receptors, these misplaced effectors
cause dysregulation and overexpression of MYC protein
 In cancers of breast, colon, lung and other tissues, MYC gene is amplified resulting in overexpression of
MYC.
 In neuroblastomas and small cell cancers of the lung, the functionally identical NMYC and LMYC are
also amplified
 In many other instances oncogenic mutations in components of upstream signaling pathways
(RAS/MAPK signaling, notch signaling, WnT signaling and Hedgehog signaling) elevate MYC protein
levels by enhancing MYC gene transcription/translation or by stabilizing MYC protein
 Several single nucleotide polymorphisms associated with an inherited risk for cancers (prostate, ovarian
carcinoma and certain leukemias) lie withing enhancer elements that flank MYC. In these instances,
higher levels of MYC RNA expression are seen in response to growth-promoting signals
Cyclins and Cyclin-Dependent kinases
 Progression of cells through the cell cycle is orchestrated by cyclin-dependent kinases which are activated by
binding to cyclins
 The CDK-cyclin complexes phosphorylate crucial target proteins that drive the cell cycle forward
 CDK inhibitors silence the CDKs and exert negative control over the cell cycle. Expression of these inhibitors
is down-regulated by mitogenic pathways that promote the progression of cell cycle
 There are two main checkpoints one at the G1/S checkpoint and the other at G2/M transition both of which are
tightly regulated by a balance of growth-promoting and growth-suppressing proteins as well as sensor of DNA
damage
 If these DNA damage sensors are activated, signals are sent to arrest cell cycle progression and if damage
cannot be repaired to initiate apoptosis
 Defects in G1/S checkpoint are more important because in addition to dysregulated growth it may also impair
DNA repair creating a mutator phenotype
 Major cancer-associated mutation that affect the G1/S checkpoint can be broadly group into two classes: Gain-
of-function mutations and loss-of-function mutations
 Gain-of-function mutations in D cyclin genes and CDK4 which promote unregulated G 1/S progression
and thus function as oncogenes
 There are three D cyclin genes (D1, D2, and D3) which are functionally interchangeable and are often
dysregulated due to acquired mutations including chromosomal translocations in lymphoid tumors and
gene amplification in a variety of solid tumors
 CDK4 gene is also amplified in melanomas, sarcomas and glioblastomas
 Mutations affecting other CDKs and cyclin E also occur but are infrequent presumably because these
factors are less important in control of G1/S transition
 Loss-of-function mutations in genes that inhibit G1/S progression include those encoding CDK inhibitors.
Examples include
 Germline mutations of p16 (CDKN2A) are present in 25% of melanoma-prone malignancies
 Somatically acquired deletions or inactivation of p16 is seen in pancreatic carcinomas (75%),
glioblastomas (40-70%), acute lymphoblastic leukemia (20-70%), non-small cell lung carcinomas (20%),
soft tissue sarcomas and bladder cancers
 RB and TP53 (tumor suppressor genes) both encode proteins that inhibit G1/S progression
Insensitivity to Growth inhibition: Tumor Suppressor Genes
 Tumor suppressor genes control cell proliferation and abnormalities in these genes can lead to failure of
growth inhibition
 Tumor suppressor proteins control a series of checkpoints that prevent uncontrolled growth
 Many tumor suppressor such as RB and P53 are part of a regulatory network that recognizes genotoxic stress
from any source and responds by shutting down cell proliferation
 Expression of oncogene in a normal cell with intact tumor suppressor gene leads to quiescence or permanent
cell-cycle arrest. Ultimately the growth inhibitory pathway may prod the cell into apoptosis
 Another set of tumor suppressors seem to be involved in cell differentiation causing cells to enter a
postmitotic differentiated pool without replicative potential
 Signals that induce growth inhibition and differentiation originate outside the cell, use receptors, signal
transducers and nuclear transcription regulators to accomplish their effects. Tumor suppressor form a portion
of these networks
 Protein products of tumor suppressor genes may function as transcription factors, cell cycle inhibitors, signal
transduction molecules, cell surface receptors and regulators of cellular responses to DNA damage
 Retinoblastoma gene is the prototype tumor suppressor gene.
 40% of retinoblastomas are familial and are transmitted as an autosomal dominant trait.
 Carriers have a 10,000-fold increased risk of developing retinoblastomas often in both eyes.
 60% occurring in the general population sporadically often in only one eye along with an increased risk of
developing osteosarcoma and other soft tissue sarcomas
 To explain these two patterns of occurrence the “two hit hypothesis of oncogenesis was proposed
 Two mutations are required in both alleles of RB to produce retinoblastoma
 In familial cases, the children inherit one abnormal and one normal RB allele. When a spontaneous
somatic mutation occurs in the normal allele retinoblastoma develops
 Most individual inheriting a defected RB allele develop unilateral or bilateral retinoblastoma
 In sporadic cases both alleles must undergo somatic mutations in the same retinoblast. The probability of
this occurring is very low which is why it is so uncommon in the general population
 An individual carrying a mutated RB allele is normal (except of the increased risk of cancer) because one
defective RB gene does not have any adverse effect on cell. Thus, although the trait is inherited in an
autosomal dominant fashion the phenotype behaves as a recessive trait
 Most other tumor suppressor genes behave in the same manner as RB genes
RB: Governor of Proliferation
 RB is a key negative regulator of G1/S cell cycle transition and is directly or indirectly inactivated in most
cancers
 In a quiescent cell it exists in an active hypophosphorylated state and an inactive hyperphosphorylated state in
cells passing through G1/S cell cycle transition
 Its function may be compromised by
 Loss-of-function mutations in both RB alleles
 A shift from active hypophosphorylated state to inactive hyperphosphorylated state as a result of gain-of-
functions that upregulate CDK/cyclin D activity or by loss of function mutations that abrogate the activity
of CDK inhibitors
 Once a cell progress through G1/S checkpoint it has to undergo mitosis
 High levels of CDK4/cyclin D, CDK6/cyclin D and CDK2/cyclin E complexes lead to hyperphosphorylation
and inhibition of RB, releasing E2F transcription factors that drive the expression of genes needed for
progression of S phase
 Growth factor signaling pathways upregulate the activity of CDK/cyclin complexes and drive the cell through
G1/S transition, while growth inhibitory pathways upregulate CDK inhibitors
 Somatic loss-of-function mutations in RB genes associated with retinoblastoma and osteosarcoma have also
been identified in other cancers such as glioblastoma, lung, breast and bladder carcinoma
 Loss of cell cycle control is central to malignant transformation. In the vast majority of cancer one of the four
key regulators (p16/INK4a, cyclin D, CDK4, RB) of cell cycle are dysregulated
 Even if RB is not mutated it may be inactivated as consequence of mutations in any one of these key
regulators or their upstream pathways
 Transforming proteins of several oncogenic viruses neutralize the growth inhibitory activities of RB
  Viral proteins (large T antigen and E7 proteins) from high-risk types of HPV (HPV16) bind to
hypophosphorylated RB at the same site used that RB uses to sequester E2 transcription factors. This binding
results in inactivation of RB and release of E2 transcription factors leading to cell cycle progression
TP53: Guardian of the Genome