10. Neoplasia GM Stom eng 2023

Department of Pathophysiology, Faculty of General Medicine and Stomatology, 2023
PATHOPHYSIOLOGY OF TUMOR GROWTH
Cancer is the second leading cause of death worldwide behind cardiovascular diseases. Even more agonizing
than the mortality rate is the emotional and physical suffering inflicted by cancers. Ten leading cancer types for the
estimated new cancer cases and deaths in USA are shown in the figure 1. The only hope for controlling cancer lies in
learning more about its causes and pathogenesis. Fortunately, great strides have been made in understanding its
molecular basis.
A neoplasm (tumor) is an abnormal mass of tissue, the growth of which is virtually autonomous and exceeds
that of normal tissues.
In general, benign tumors are designated by attaching the suffix -oma to the name of the cell type from which
the tumor originates. For example, a benign tumor arising in fibrous tissue is called a fibroma, whereas a benign
cartilaginous tumor is a chondroma.
Malignant tumors are collectively referred to as cancers, derived from the Latin word for crab, because they
tend to adhere to any part that they seize on in an obstinate manner. Malignant tumors arising in solid mesenchymal
tissues are usually called sarcomas, whereas those arising from blood-forming cells are designated leukemias (literally,
white blood) or lymphomas (tumors of lymphocytes). Malignant neoplasms of epithelial cell origin are called
carcinomas, etc.
Figure 1. Ten leading cancer types for the estimated new cancer cases and deaths by sex, United States, 2023. Estimates are rounded to the nearest
10, and cases exclude basal cell and squamous cell skin cancers and in situ carcinoma except urinary bladder. Ranking is based on modeled projections
and may differ from the most recent observed data.. From Siegel RL, Miller KD, Wagle NS, Jemal A. Cancer statistics, 2023. CA Cancer J Clin.
2023;73(1):17-48.
1
Characteristics of benign and malignant neoplasms
Benign and malignant tumors can be distinguished from one another based on the degree of differentiation,
local invasiveness, and distant spread.
 Benign tumors resemble the tissue of origin and are well differentiated; malignant tumors are less well
differentiated or completely undifferentiated (anaplastic).
 Benign tumors are more likely to retain functions of their cells of origin, whereas malignant tumors sometimes
acquire unexpected functions due to derangements in differentiation.
 Benign tumors are slow growing, while malignant tumors generally grow faster.
 Benign tumors are circumscribed and have a capsule; malignant tumors are poorly circumscribed and invade
surrounding normal tissues.
 Benign tumors remain localized at the site of origin; malignant tumors metastasize to distant sites. Carcinomas tend
to spread via lymphatics, whereas sarcomas prefer the hematogenous route.
Etiology
Although both genetic and environmental factors contribute, environmental influences are the dominant risk
factors for most cancers. The best-established environmental risk factors are the following.
1. Infectious agents. About 15% of all cancers worldwide are caused directly or indirectly by infectious agents. For
example, human papillomavirus (HPV), an agent spread through sexual contact, has a causative role in the majority of
cervical carcinomas. Specific infectious agents and their associated cancers are discussed later. According to WHO,
vaccination against these HPV and hepatitis B viruses could prevent 1 million cancer cases each year.
2. Smoking. It increases risk of cancer of the mouth, pharynx, larynx, esophagus, pancreas, bladder, and most
significantly, about 90% of lung cancer cases are related to smoking. Tobacco use is the single most important risk
factor for cancer and is responsible for approximately 22% of cancer-related deaths globally.
3. Alcohol consumption. Alcohol abuse increases the risk of carcinoma of the oropharynx (excluding lip), larynx, and
esophagus and, by the development of alcoholic cirrhosis, hepatocellular carcinoma. Moreover, the risk of cancers in
the upper airways and digestive tract imposed by alcohol is increased synergistically when combined with tobacco use.
4. Diet: grilled meat, high-fat diet, low fruit and vegetable intake.
5. Ecological factors: urban pollution, pesticides and nitrates in food, exposure to aniline, asbestos in the workplace,
exposure to ultraviolet [UV], X-rays and other types of ionizing radiation.
6. Age: most carcinomas occur in the later years of life (>55 Years).
7. Obesity: studies showed that rate of death from cancers in obese men is about twice more than in thin men and is
more by 62% in obese females. Obesity is a risk factor for breast, colorectal, and ovarian cancer. Lack of physical activity
also predisposes to cancer.
8. Genetic predisposition: in most of the cases tumors occur sporadic without evident genetic predisposition. But there
are cases of hereditary disorders with very high risk of cancers in members of family, e.g. familial adenomatous
polyposis (affecting colon), familial breast cancer.
9. Chronic inflammatory disorders and immunodeficiency states. Chronic inflammatory disorders are associated with
increased cellular replication, which appears to create a “fertile” soil for the development of malignant tumors. Indeed,
repeated rounds of cell division may be required for neoplastic transformation, as proliferating cells are most at risk for
somatic mutations that lead to carcinogenesis. Immunodeficiency states predispose to virus-induced cancers.
2
As you see, main risk factors of cancer are related to lifestyle. The healthy lifestyle recommendations are
practical and achievable steps that everyone can take to reduce their risk of cancer.
Factors that increase the risk of neoplasms are called carcinogens. By their nature carcinogens are classified as
physical, chemical and biological.
Physical carcinogens are radiation, thermal and mechanical factors. Radiation, whatever its source (UV rays of
sunlight, radiographs, nuclear fission, radionuclides), is an established carcinogen. A follow-up study of survivors of
the atomic bombs dropped on Hiroshima and Nagasaki disclosed a markedly increased incidence of leukemia (blood
cancer) after an average latent period of about 7 years, as well as increased mortality rates for thyroid, breast, colon,
and lung carcinomas. UV radiation is associated with skin cancer. Thermal and mechanical factors, if they act
repeatedly, cause chronic inflammation, which may increase risk of cancer.
Biological carcinogens are oncogenic viruses (shown in the table) and bacteria.
Oncogenic virus Tumor caused by the virus Type of the virus

HTLV-1 ( human T-lymphotropic virus type 1) Human T-Cell Leukemia RNA virus
Hepatitis C virus hepatocellular carcinoma RNA virus
(indirectly)
Hepatitis B virus hepatocellular carcinoma DNA virus
(indirectly)
Epstein-Barr virus nasopharingeal carcinoma DNA virus
and Burkitt lymphoma
Herpes virus 8 Kaposi sarcoma DNA virus
Human papillomavirus (HPV) uterine cervical cancer, anal DNA virus
cancer
Example of oncogenic bacteria is Helicobacter pylori, which is implicated in the genesis of both gastric
adenocarcinomas and gastric lymphomas.
Chemical carcinogens can damage DNA, leading to mutations and eventually cancer. There are direct-acting
agents (e.g., alkylating agents used for chemotherapy) and indirect-acting agents (e.g., benzo[a]pyrene, azo dyes,
aflatoxin1). Direct-acting agents do not require metabolic conversion to become carcinogenic, while most chemical
carcinogens are indirect-acting agents and require metabolic activation for conversion into ultimate carcinogens. For
example, benzo[a]pyrene (the active component of soot, which Potts2 showed to be carcinogenic), are formed during
the high-temperature combustion of tobacco in cigarettes and are implicated in the causation of lung cancer. Polycyclic
hydrocarbons also are produced from animal fats during the process of broiling or grilling meats and are present in
smoked meats and fish. Most indirect carcinogens are metabolized by cytochrome P-450–dependent monooxygenases.
The genes that encode these enzymes are polymorphic, and the activity and inducibility of these enzymes vary
significantly among individuals. Because these enzymes are essential for the activation of procarcinogens, the
susceptibility to carcinogenesis is related in part to the particular polymorphic variants that an individual inherits.
After exposure of a cell to a mutagen or an initiator, tumorigenesis can be enhanced by exposure to promoters, which
stimulate proliferation of the mutated cells.
1
aflatoxin B1, a naturally occurring agent produced by some strains of the mold Aspergillus. Aspergillus grows on improperly stored grains and
nuts, and there is a strong correlation between the dietary level of this food contaminant and the incidence of hepatocellular carcinoma in parts
of Africa and the Far East.
2
More than 200 years ago, the London surgeon Sir Percival Pott correctly attributed scrotal skin cancer in chimney sweeps to chronic exposure
to soot.
3
Pathogenesis: molecular basis of cancer
Evidence for the genetic origins of cancer has been building up for over several decades and certain “genomic
themes” have emerged that are likely relevant to every cancer.
 Nonlethal genetic damage lies at the heart of carcinogenesis. The initial damage (or mutation) may be caused by
exposure to carcinogens, may be inherited in the germline, or may be spontaneous and random, falling into the
category of “bad luck.”
 Carcinogenesis results from the accumulation of complementary mutations in a stepwise fashion over time.
 A tumor is formed by the clonal expansion of a single precursor cell that has incurred genetic damage (i.e., tumors
are clonal). Alterations in DNA are passed to daughter cells, and thus all cells within an individual tumor share the
same set of mutations that were present at the moment of transformation.
 Four classes of normal regulatory genes—the growth promoting proto-oncogenes, the growth-inhibiting tumor
suppressor genes, genes that regulate programmed cell death (apoptosis), and genes involved in DNA repair—are
the principal targets of cancer-causing mutations. In the following section, they are discussed in more detail.
Proto-oncogenes, oncogenes, and oncoproteins

Proto-oncogenes are normal genes which encode proteins involved in signaling pathways of cell proliferation.
Under physiologic conditions growth factor signaling pathways can be resolved into the following steps:
 The binding of a growth factor to its specific receptor,
 Transient and limited activation of the growth factor receptor, which, in turn, activates several cytoplasmic signal-
transducing proteins (second messengers),
 Transmission of the transduced signal to the nucleus,
 Induction and activation of nuclear regulatory factors that initiate DNA transcription.
 Expression of factors that promote entry and progression of the cell into the cell cycle, resulting in cell division.
Thus, proto-oncogenes encode growth factors, growth factor receptors, signal transducers, transcription
factors, or cell cycle components.
Genes that promote abnormal, uncontrolled, autonomous cell growth in cancer cells are called oncogenes.
Oncogenes are created by mutations in proto-oncogenes and encode proteins called oncoproteins that have the ability to
promote cell growth in the absence of normal growth-promoting signals.
The corresponding oncogenes generally encode oncoproteins that serve functions similar to their normal
counterparts, with the important difference that they are usually constitutively active. As a result of this constitutive
activity, oncoproteins endow cells with self-sufficiency in growth. Mechanisms of transformation of proto-oncogene
into an oncogene are the following:
• Gene amplification, which leads to increased production of oncoproteins (problem of quantity).
• Gene structural alteration (problem of quality) leads to constitutive activation of proliferative signaling. The classical
example of this scenario is point mutation in RAS protein. RAS proteins are membrane-associated small G proteins that bind
guanosine nucleotides GTP and GDP. When growth factor binds to growth factor receptor (tyrosine kinase), it leads to
transient activation of RAS and binding of GTP (Figure 2). Activated RAS stimulates downstream signaling pathway of
secondary messengers (e.g. mitogen-activated protein kinase (MAPK) pathway) leading to activation of several transcription
factors (e.g. MYC) that turn on genes that support rapid cell growth. Activation of RAS is transient because RAS has an
intrinsic GTPase activity that is accelerated by GTPase-activating proteins (GAPs), which bind to active RAS and augment
its GTPase activity by more than 1000-fold, thereby terminating signal transduction. Thus, GAPs prevent uncontrolled RAS
activity. Hydrolysis of GTP leads to inactivation of RAS. Several distinct RAS point mutations have been identified in cancer
4
cells that markedly reduce the GTPase activity of the RAS protein. As a result, these mutated forms of RAS are trapped in
the activated GTP-bound form and the cell receives pro-growth signals continuously.
Figure 2. Growth factor signaling pathways in normal cell (left) and

cancer (right). Growth factor receptors, RAS, PI3K, MYC, and D cyclins
are oncoproteins that are activated by mutations in various cancers.
GTPase-activating proteins (GAPs) apply brakes to RAS activation,
and phosphatase and tensinhomologue (PTEN) serves the same
function for PI3K. GDP, Guanosine diphosphate; GTP, guanosine
triphosphate.
Tumor Suppressor Genes

Whereas oncogenes drive the proliferation of cells, the products of most tumor suppressor genes apply brakes
to cell proliferation, and abnormalities in these genes lead to failure of growth inhibition, another fundamental
hallmark of carcinogenesis. Tumor suppressor proteins form a network of checkpoints that prevent uncontrolled
growth (Figure 3).
Cell cycle control. There are two main cell cycle checkpoints, one at the G1/S transition and the other at the
G2/M transition, each of which is tightly regulated by a balance of growth promoting and growth suppressing factors,
as well as by sensors of DNA damage. These quality control checkpoints ensure that cells with genetic imperfections
do not complete replication. The G1/S checkpoint monitors DNA integrity before irreversibly committing cellular
resources to DNA replication. Later in the cell cycle, the G2/M checkpoint insures that there has been accurate genetic
replication before the cell actually divides.
Positive regulators of cell cycle. Growth factors transduce signals that stimulate the orderly progression of cells
through the various phases of the cell cycle. Progression of cells through the cell cycle is orchestrated by cyclins and
cyclin dependent kinases (CDKs). The CDK-cyclin complexes phosphorylate crucial target proteins that drive cells
forward through the cell cycle.
5
Negative regulators of cell cycle.
The best understood negative regulatory
molecules are tumor suppressor proteins
retinoblastoma protein (Rb3), p53, and p21.
The frequent loss of function of these genes
in human tumors reflects their critical role
in prevention of cancer development.
Much of what is known about cell cycle
regulation comes from research conducted
with cells that have lost regulatory control.
Rb, p53, and p21 act primarily at the
G1/S checkpoint.
p53 (Figure 4) is the guardian of the
genome. p53 is a multi-functional protein
(a transcription factor) that acts when there Figure 3. Cell cycle.
is damaged DNA in cells that are
undergoing the preparatory processes during G1. Once activated, p53 prevents neoplastic transformation by inducing
either transient cell cycle arrest, senescence (permanent cell cycle arrest), or programmed cell death (apoptosis).
• p53-mediated cell cycle arrest occurs late in the G1 phase and is caused by p53-dependent transcription of a gene,
which encodes p21. p21 inhibits CDK4/D cyclin complex and blocks the progression of cells from G1 phase to S phase.
This pause in cell cycling is welcome, as it gives the cells “breathing time” to repair DNA damage. p53 also helps the
process by inducing certain proteins, that enhance DNA repair. If DNA damage is repaired successfully, the signals
responsible for p53 stabilization cease and p53 levels fall, releasing the cell cycle block. The cells may then revert to a
normal state.
• p53-induced senescence. Senescence is a state of permanent cell cycle arrest characterized by specific changes in
morphology and gene expression that differentiate it from reversible cell cycle arrest4. The senescent cells, while not normal,
are blocked from developing into tumors.
• p53-induced apoptosis. Apoptosis of cells with irreversible DNA damage is the ultimate protective mechanism against
neoplastic transformation. p53 directs the transcription of several pro-apoptotic genes (such as bax and PUMA [p53
upregulated modulator of apoptosis]) involved in cell death via the intrinsic (mitochondrial) pathway.
With loss of p53 function, DNA damage goes unrepaired, mutations are accumulated, and the cell marches
blindly along a dangerous path leading to malignant transformation.
3
when the RB is mutated tumor of retinoblasts - retinoblastoma - develops.
4How cells become fixed in the senescence state is unclear. One plausible idea is that senescence is the product of epigenetic
changes that result in the formation of heterochromatin at key loci, including genes that are required for progression of cells from
the G1 phase into S phase.
6
Figure 4. p53 is the guardian of the genome.
Rb is a key negative regulator of the G1 /S cell cycle transition. The decision of a cell to progress from G1 into
S is of great importance, as once a cell enters S phase it is obligated to complete mitosis. In the active, dephosphorylated
state, Rb represses gene transcription, required for transition from G1 to S phase. Growth factor signaling pathways
generally upregulate the activity of CDK/cyclin complexes, which leads to hyperphosphorylation and inhibition of RB.
Growth inhibitors tip the balance the other way by upregulating CDK inhibitors. RB is the point of integration of these
opposing signals, making it a key player in regulation of cell cycle progression.
Mutations that affect tumor suppressor genes generally cause a “loss-of-function,” and in most instances both
alleles must be damaged before transformation can occur. Thus, mutated tumor suppressor genes usually behave in a
recessive fashion. However, there are exceptions: sometimes loss of only a single tumor suppressor gene allele (a state
termed haploinsufficiency) reduces the activity of the encoded protein enough to release the brakes on cell
proliferation and survival. Such a finding indicates that two “doses” of the gene are essential for normal function.
The transforming proteins of several oncogenic DNA viruses also act, in part, by neutralizing the growth-
inhibitory activities of RB and p53. For example, the RB protein is functionally inactivated by the binding of HPV E7
protein, while E6 binds p53 and promote its degradation.
7
While tumor suppressors were initially thought of narrowly as proteins that put the brakes on cell cycle
progression, it is now appreciated that some tumor suppressors prevent cellular transformation through other
mechanisms such as by altering cell metabolism or by ensuring genomic stability. Thus, a more inclusive definition of
a tumor suppressor is simply a protein or gene that opposes any of the various hallmarks of cancer. From this perspective,
the following proteins are also tumor suppressors.
APC (Figure 5) (Adenomatous
polyposis coli) is a member of the class
of tumor suppressors that function by
downregulating growth-promoting
signaling pathways. Germline loss-of-
function mutations involving the APC
locus are associated with familial
adenomatous polyposis. The APC
gene exerts anti-proliferative
actions by regulating the
destruction of the cytoplasmic
protein β-catenin. With a loss of APC, Figure 5․ The role of adenomatous polyposis coli (APC) in regulating the stability and function of β-
β-catenin is not destroyed, and it is catenin.
translocated to the nucleus, Here, it forms a transcription activation complex with a DNA-binding factor called TCF
that promotes the growth of colonic epithelial cells by increasing the expression of MYC, cyclin D1, and other genes.
This is why APC is considered as a gatekeeper of colonic neoplasia.
VHL (von Hippel–Lindau) promotes HIF1α ubiquitination and proteasomal degradation in normoxic
conditions. Loss-of-function mutations in VHL results in HIF1α accumulation. It turns on target genes, including genes
encoding vascular endothelial growth factor (VEGF), a critical angiogenesis factor; glucose transporter GLUT1 and
glycolytic enzymes, factors that contribute to Warburg effect (described
later).
Genes that regulate apoptosis
A cell with genomic injury can be induced to die, eliminating
the chance that such a cell might go on to give rise to a neoplasm. A
variety of signals, including DNA damage, deregulation of some of the
most potent oncoproteins such as MYC, and loss of adhesion to the
basement membrane (termed anoikis), can trigger apoptosis. Thus,
apoptosis is a barrier that must be surmounted for cancer to develop and
progress. The two major mechanisms by which apoptosis is avoided by
cancer cells are the following (Figure 6):
• Loss of pro-apoptotic molecules (p53, bax, bak, etc.).
• Overexpression of anti-apoptotic molecules, such as bcl-2. (bcl-2
derives its name from B-cell lymphoma, a cancer, characterized by
overproduction of this protein).
Figure 6․ Cancer cell avoids apoptosis by two major

mechanisms.
8
DNA repair genes
Although humans literally swim in environmental agents that are mutagenic (e.g., chemicals, radiation,
sunlight), cancers are relatively rare outcomes of these encounters. This state of affairs results from the ability of normal
cells to repair DNA damage, the death of cells with irreparable damage, immune surveillance and other mechanisms.
We have previously discussed the role of p53 in protecting the genome from potentially oncogenic damage. The
importance of DNA repair in maintaining the integrity of the genome is further highlighted by several inherited
disorders in which genes that encode proteins involved in DNA repair are defective. Individuals born with such
inherited defects in DNA repair proteins are at a greatly increased risk of developing cancer. Loss-of-function mutations
in DNA-repair genes themselves are not oncogenic, but their abnormalities greatly enhance the occurrence of
mutations in other genes by impairing the ability of the cell to recognize and repair DNA damage. As a result, affected
cells acquire mutations at an accelerated rate, a state referred to as genomic instability.
Inherited disorders of DNA repairing system include xeroderma pigmentosum and familial breast cancers.
Patients with xeroderma pigmentosum have a defect in the nucleotide excision repair pathway and are at increased
risk for the development of cancers of the skin exposed to UV light because of an inability to repair pyrimidine dimers.
BRCA1 and BRCA2, which are mutated in familial breast cancers, are involved in DNA repair (homologous
recombination repair).
Role of epigenetic alterations in carcinogenesis

Neoplastic transformation of a cell
may result not only from mutations in
abovementioned genes. It is increasingly
apparent that in addition to DNA mutations,
epigenetic aberrations also contribute to the
malignant properties of cancer cells.
Epigenetic modifications include DNA
methylation, which tends to silence gene
expression, modifications of histones,
which depending on their nature may
either enhance or dampen gene expression,
and inhibition of protein translation by
microRNAs. Together, DNA methylation
and histone modifications dictate which
genes are expressed. Thus, genes of tumor
suppressors, proapoptotic proteins and
DNA repair enzymes can be silenced by
DNA methylation, and vice versa,
demethylation of protooncogenes will favor
their transcription. Increased production of
appropriate microRNAs can stop translation Figure 7. Role of miRNAs in neoplastic growth
of tumor suppressors, proapoptotic proteins and DNA repair enzymes, whereas loss of microRNAs which normally suppress
translation of growth promoting factors will lead to overproduction of the latter (Figure 7). The increasing awareness of the
role of epigenetic alterations in cancer has revealed a new path forward for cancer treatment; unlike DNA mutations,
9
epigenetic changes are potentially reversible by drugs that inhibit DNA-modifying or histone-modifying factors. Thus, there
is great interest in treating cancers with drugs that correct epigenetic abnormalities.
Tumor progression
Once established,
tumors evolve genetically
during their outgrowth and
progression under the
pressure of Darwinian
selection (survival of the
fittest). Early on, all of the
cells in a tumor are
genetically identical, being
the progeny of a single
Figure 8. Tumor progression.
founding transformed cell.
However, by the time a tumor comes to clinical attention (generally when it attains a mass of about 1 gm, or about 109
cells), it has gone through a minimum of 30 cell doublings. During this process, there is competition among tumor cells
for access to nutrients and microenvironmental niches, and subclones with the capacity to overgrow their predecessors
tend to “win” this Darwinian contest and dominate the tumor mass, only to be replaced by other, still malignant
subclones. This pernicious tendency of tumors to become more aggressive over time is referred to as tumor progression
(Figure 8). As a result, even though malignant tumors are clonal in origin, by the time they become clinically evident
their constituent cells are often extremely heterogeneous genetically. Selection of the fittest cells can explain not only
the natural history of cancer, but also changes in tumor behavior following therapy. One of the most profound selective
pressures that cancer cells face is effective chemotherapy or radiotherapy given by treating physicians. Tumors that
recur after therapy are almost always found to be resistant if the same treatment is given again, presumably because
therapy selects for preexistent subclones that, by chance, have a genotype that allows them to survive.
Cellular and Molecular Hallmarks of Cancer
Malignant neoplasms have several phenotypic attributes referred to as cancer hallmarks. These changes that
also are therapeutic targets are illustrated in the figure (Figure 9):
1. Self-sufficiency in growth signals. Tumors have the capacity to proliferate without external stimuli, usually
as a consequence of oncogene activation.
2. Insensitivity to growth-inhibitory signals. Tumors may not respond to molecules that inhibit the proliferation
of normal cells, usually because of inactivation of tumor suppressor genes that encode components of these growth
inhibitory pathways.
3. Evasion of apoptosis. Tumor cells frequently contain mutations in genes that result in resistance to apoptotic
cell death.
4. Genome instability due to defects of DNA repairing system. We have described first four hallmarks earlier.
In the following section, remaining six hallmarks of cancer cells are discussed in more detail.
10
Figure 9. Hallmarks of cancer. (Modified from Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation, Cell, 2011.)
5. Altered cellular metabolism. Even in the presence of ample oxygen, cancer cells demonstrate a distinctive
form of cellular metabolism characterized by high levels of glucose uptake and increased conversion of glucose to
lactate via the glycolytic pathway. This phenomenon, called the Warburg effect and also known as aerobic glycolysis,
has been recognized for many years (indeed, Otto Warburg received the Nobel Prize in 1931 for discovery of the effect
that bears his name). At the heart of the Warburg effect lies a simple question: why is it advantageous for a cancer cell
to rely on seemingly inefficient glycolysis (which generates two molecules of ATP per molecule of glucose) instead of
oxidative phosphorylation (which generates up to 36 molecules of ATP per molecule of glucose)? While pondering this
question, it is important to recognize that rapidly growing normal cells, such as in embryonic tissues, also rely on
aerobic fermentation. Thus, “Warburg metabolism” is not cancer specific, but instead is a general property of growing
cells that becomes “fixed” in cancer cells. The answer to this riddle is simple: aerobic glycolysis provides rapidly dividing
tumor cells with metabolic intermediates that are needed for the synthesis of cellular components, whereas
mitochondrial oxidative phosphorylation does not. The reason growing cells rely on aerobic glycolysis becomes readily
apparent when one considers that a growing cell has a strict biosynthetic requirement; it must duplicate all of its
cellular components - DNA, RNA, proteins, lipid, and organelles—before it can divide and produce two daughter cells.
While “pure” oxidative phosphorylation yields abundant ATP, it fails to produce any carbon moieties that can be used
to build cellular components that are needed for growth (proteins, lipids, and nucleic acids). Even cells that are not
actively growing must shunt some metabolic intermediates away from oxidative phosphorylation in order to synthesize
macromolecules that are needed for cellular maintenance. So how is this profound reprogramming of metabolism, the
11
Warburg effect, triggered in growing normal and malignant cells? As might be guessed, metabolic reprogramming is
produced by signaling cascades downstream of growth factor receptors, the very same pathways that are deregulated by
mutations in oncogenes and tumors suppressor genes in cancers. Many oncoproteins (RAS, MYC, mutated growth factor
receptors) induce or contribute to Warburg metabolism, and many tumor suppressors (e.g. p53) oppose it.
Clinically, the “glucose-hunger” of tumors is used to visualize tumors via positron emission tomography (PET)
scanning, in which patients are injected with 18F-fluorodeoxyglucose, a nonmetabolizable derivative of glucose that
is preferentially taken up into tumor cells.
6. Limitless replicative potential (immortality). All cancers contain cells that are immortal and have limitless replicative
potential. How can it be that cancer cells have seemingly discovered the proverbial fountain of eternal youth? The
answers are not completely known, but one of the major mechanisms is related to telomerase activity. Most normal
human cells have the capacity to divide 60 to 70 times (the Hayflick limit). After this, the cells eventually enter into a
phase referred to as mitotic crisis and die. This phenomenon has been ascribed to progressive shortening of telomeres
at the ends of chromosomes. Telomeres are special DNA sequences at the ends of chromosomes that bind several types
of protective protein complexes (shelterins), preventing the telomere ends from being recognized as break points by
the DNA repair machinery (which would result in “repair” by nonhomologous end-joining). Most somatic cells do not
express telomerase, the enzyme that is responsible for the maintenance of telomeres, and with each cell division their
telomeres shorten. When the telomeric DNA is eroded, the exposed chromosome ends are “sensed” as double-stranded
DNA breaks. If the affected cells have functional p53, the cell arrests its growth and may undergo apoptosis, but if p53
is dysfunctional, the nonhomologous end-joining pathway is activated and may join the “naked” ends of two
chromosomes. This results in dicentric chromosomes that are pulled apart at anaphase, resulting in new double-
stranded DNA breaks. The snowballing genomic damage caused by repeated “bridge-fusion breakage” cycles eventually
produces mitotic catastrophe and cell death. However, if cells in crisis reactivate telomerase, the cells can restore their
telomeres and survive; such cells may have suffered damage to oncogenes and tumor suppressor genes during crisis and
Figure 10. Escape of cells from senescence and mitotic catastrophe caused by telomere shortening.
12
are at high risk for malignant transformation (Figure 10). Alternatively, cancers may arise from stem cells, which are
long-lived in part because they express telomerase.
7. Sustained angiogenesis. Even if a solid tumor possesses all of the genetic aberrations that are required for
malignant transformation, it cannot enlarge beyond 1 to 2 mm in diameter unless it has the capacity to induce
angiogenesis (like normal tissues, tumors require delivery of oxygen and nutrients and removal of waste products;
presumably the 1- to 2-mm zone represents the maximal distance across which oxygen, nutrients, and waste can diffuse
from blood vessels). Early in their development, most human tumors do not induce angiogenesis. Starved of nutrients,
these tumors remain small or in situ, possibly for years, until an angiogenic switch terminates this stage of vascular
quiescence. Growing cancers stimulate neoangiogenesis, during which vessels sprout from previously existing
capillaries. Neovascularization has a dual effect on tumor growth: perfusion supplies needed nutrients and oxygen, and
newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors. New vessels
are leaky and dilated, and have a haphazard pattern of connection. By permitting tumor cells access to these abnormal
vessels, angiogenesis also contributes to metastasis. Angiogenesis is thus an essential facet of malignancy. How do
growing tumors develop a blood supply? The current paradigm is that angiogenesis is controlled by a balance between
angiogenesis promoters and inhibitors; in angiogenic tumors this balance is skewed in favor of promoters. These factors
may be produced by the tumor cells themselves or by inflammatory cells (e.g., macrophages) or other stromal cells
associated with the tumors. The major mechanism of angiogenesis is relative lack of oxygen due to hypoxia which
stabilizes HIF1α, an oxygen-sensitive transcription factor, which then activates the transcription of the proangiogenic
cytokine VEGF. VEGF creates an angiogenic gradient that stimulates the proliferation of endothelial cells and guides
the growth of new vessels toward the tumor.
8. Ability to invade and metastasize. Invasion and metastasis are the results of complex interactions between
cancer cells and stroma and are the major causes of cancer-related morbidity and mortality (Figure 11). A carcinoma
cell must first dissociate from other cancer cells, breach the underlying basement membrane, then traverse the
interstitial connective tissue, and ultimately gain access to the circulation by penetrating the vascular basement
membrane. This process is repeated in reverse when tumor cell emboli extravasate at a distant site.
1) Dissociation of cancer cells from one another is often the result of alterations in intercellular adhesion molecules.
Normal epithelial cells are tightly glued to each other and the extracellular matrix (ECM) by a variety of adhesion
molecules. Cell-cell interactions are mediated by the cadherin family of transmembrane glycoproteins. E-cadherins
mediate the homotypic adhesion of epithelial cells, serving to both hold the cells together and to relay signals between
the cells. In several epithelial tumors, including adenocarcinomas of the colon, stomach, and breast, E-cadherin
function is lost. Presumably, this reduces the ability of cells to adhere to each other and facilitates their detachment.
2) Degradation of the basement membrane and interstitial connective tissue. Tumor cells may accomplish this by either
secreting proteolytic enzymes themselves or by inducing stromal cells (e.g., fibroblasts and inflammatory cells) to
elaborate proteases, such as matrix metalloproteinases (MMPs). Normal epithelial cells have receptors, such as
integrins, for basement membrane laminin and collagens at basal surface; these receptors help to maintain the cells in
a resting, differentiated state. Loss of adhesion in normal cells leads to induction of apoptosis (the term anoikis, “the
state of being without a home”, is applied in the case of apoptosis that occurs in anchorage-dependent cells when they
detach from the basement membrane) while, not surprisingly, tumor cells are resistant to this form of cell death.
3) Migration of tumor cells through the degraded basement membranes and zones of matrix proteolysis. Migration is a
multistep process directed by tumor cell-derived cytokines (autocrine motility factors), cleavage products of matrix
components (e.g., collagen, laminin) and some growth factors liberated from cleaved matrix. Stromal cells (e.g.,
fibroblasts and inflammatory cells) also “lend a helping hand” by production of paracrine signals of cell motility. Thus,
13
tumor cells reside in a complex and ever-changing milieu composed of ECM, growth factors, fibroblasts, and immune
cells, with significant cross-talk among all the components. It is easy to imagine that tumors come to be dominated by
subclones that are most successful at co-opting this environment to their own malignant purposes.
Figure 11. Invasion and metastasis.

4) Once in the circulation, tumor cells are vulnerable to destruction by a variety of mechanisms, e.g. immune defense.
So, tumor cells can mask themselves by adhesion to platelets and clotting factors. Formation of platelet-tumor
aggregates may enhance tumor cell survival and implantability. Arrest and extravasation of tumor emboli at distant
sites involves adhesion to the endothelium, followed by egress through the basement membrane. Adhesion molecules
and proteolytic enzymes, involved in these processes, were discussed earlier.
Among candidates for metastasis oncogenes are SNAIL, SLUG, Zeb1 and TWIST, which encode transcription factors
promoting epithelial-to-mesenchymal transition (EMT), a developmental program that is normally employed during
embryogenesis and in adults for wound healing and is hijacked by carcinoma cells, endowing them with multiple
malignant traits associated with the loss of epithelial properties and the acquisition of certain mesenchymal features in
their stead. In EMT, carcinoma cells downregulate certain epithelial markers (e.g., E-cadherin) and upregulate certain
mesenchymal markers (e.g., vimentin and smooth muscle actin). These changes are believed to favor the development
of a promigratory phenotype that is essential for metastasis.
9. Tumor promoting inflammation. Infiltrating cancers provoke a chronic inflammatory reaction, leading some
to liken them to “wounds that do not heal.” In patients with advanced cancers, this inflammatory reaction can be so
extensive as to cause systemic signs and symptoms, such as fever, anemia, and cachexia. Inflammatory cells modify the
local tumor microenvironment to enable many of the hallmarks of cancer. These effects may stem from direct
14
interactions between inflammatory cells and tumor cells, or through indirect effects of inflammatory cells on other
resident stromal cells, particularly cancer-associated fibroblasts and endothelial cells. Proposed cancer-enabling effects
of inflammatory cells and resident stromal cells include the following:
•Release of factors that promote proliferation.
•Removal of growth suppressors. As mentioned, the growth of epithelial cells is suppressed by cell-cell and cell-ECM
interactions. Proteases released by inflammatory cells can degrade the adhesion molecules that mediate these
interactions, removing a barrier to growth.
•Enhanced resistance to cell death. Recall that detachment of epithelial cells from basement membranes and from cell-
cell interactions can lead to cell death called anoikis. It is suspected that tumor-associated macrophages may prevent
anoikis by expressing adhesion molecules such as integrins that interact with tumor cells and promote cell survival in
the face of stresses.
•Inducing angiogenesis. Inflammatory cells release angiogenic factors, including VEGF.
•Activating invasion and metastasis. Macrophages release proteases (fostering invasion by remodeling the ECM), and
cytokines stimulating tumor cell motility. Factors released from stromal cells, such as transforming growth factor β
(TGF-β), may promote epithelial-mesenchymal transitions, a key event in the process of invasion and metastasis.
•Evading immune destruction. A variety of factors released by macrophages and other stromal cells (including TGF-β
and other factors) contribute to the immunosuppressive microenvironment of tumors, that favor the recruitment of
immunosuppressive T regulatory cells or suppress the function of CD8+ cytotoxic T cells.
10. Ability to evade the host immune response. Tumors produce a number of factors that promote immune
tolerance and immune suppression, and that therapeutic agents that neutralize these factors can lead to tumor
regression, even in patients with advanced cancers. These encouraging clinical responses constitute strong evidence
that evasion of host immunity is indeed a hallmark of cancers. It is evident, then, that tumor cells must develop
mechanisms to escape or evade the immune response:
•Selective outgrowth of antigen-negative variants. During tumor progression, strongly immunogenic subclones may be
eliminated, an example of immunoediting.
•Loss of MHC molecules. Tumor cells may fail to express normal levels of HLA class I molecules, thereby escaping
attack by cytotoxic T cells. Such cells, however, may be killed by NK cells.
•Activation of immunoregulatory pathways. An important emerging concept is that tumor cells actively inhibit tumor
immunity by engaging normal pathways of immune regulation that serve as “checkpoints” in immune responses.
Through a variety of mechanisms, tumor cells may downregulate the expression of costimulatory factors on antigen-
presenting cells, such as dendritic cells; as a result, the antigen presenting cells fail to engage the stimulatory receptor
CD28 and instead activate the inhibitory receptor CTLA-4 on effector T cells.
•Secretion of immunosuppressive factors by cancer cells. Tumors may secrete several products that inhibit the host
immune response, such as TGF-β and interleukin-10.
•Induction of regulatory T cells (Tregs). Some studies suggest that tumors produce factors that favor the development
of immunosuppressive T regs, which could also contribute to “immunoevasion.”
15
Hallmarks of Cancer: New Dimensions

On the very first day of 2022 the journal “Cancer
Discovery” published an article by Hanahan, who suggested
4 additional hallmarks of cancer based on the summary of
discoveries in recent decade (Figure 12). The proposed
features are: “unlocking phenotypic plasticity”,
“nonmutational epigenetic reprogramming”, “polymorphic
microbiomes”, and “senescent cells”. Here we will very
briefly address them.
Normal cells after division usually differentiate and
become professionals, required by the given tissue. As such,
the end result of cellular differentiation is in most cases
antiproliferative and constitutes a clear barrier to the
continuing proliferation that is necessary for neoplasia.
Cancer cells unlock phenotypic plasticity: they may
dedifferentiate back or block differentiation (anaplasia) or Figure 12․ Four new hallmarks of cancer proposed by
Hanahan. Douglas Hanahan; Hallmarks of Cancer: New
even transdifferentiate (metaplasia). A prominent example
Dimensions. Cancer Discov 1 January 2022; 12 (1): 31–46
is Barrett’s esophagus, where chronic inflammation of the
stratified squamous epithelium of the esophagus induces transdifferentiation into a simple columnar epithelium that is
characteristic of the intestine, thereby facilitating the subsequent development of adenocarcinomas, and not the
squamous cell carcinomas that would be anticipated to arise from this squamous epithelium.
In the previous section, we have already acknowledged the role of gene methylations and miRNAs in turning off
the suppressor genes. Now it is proposed to be considered as an independent hallmark since more mechanisms
underlying such nonmutational epigenetic reprogramming become clarified. For example, one of the abovementioned
master regulators of the EMT, ZEB1, has been recently shown to induce the expression of a histone methyltransferase,
SETD1B, that in turn sustains ZEB1 expression in a positive feedback loop that maintains the (invasive) EMT regulatory
state.
Most evidence for considering “polymorphic microbiomes” as a hallmark comes from colorectal cancer studies. In
recent years, persuasive functional studies, involving fecal transplants from colon tumor-bearing patients and mice into
recipient mice predisposed to develop colon cancer have established a principle: there are both cancer-protective and
tumor-promoting microbiomes, involving particular bacterial species, which can modulate the incidence and
pathogenesis of colon tumors. The mechanisms by which microbiota impart these modulatory roles are still being
elucidated, but two general effects are increasingly well-established for tumor-promoting microbiomes and in some
cases for specific tumor-promoting bacterial species. The first effect is mutagenesis of the colonic epithelium,
consequent to the production of bacterial toxins and other molecules that either damage DNA directly, or disrupt the
systems that maintain genomic integrity, or stress cells in other ways that indirectly impair the fidelity of DNA
replication and repair. An example: some stains of E. coli demonstrably mutagenize the human genome and is
implicated in conveying hallmark-enabling mutations. Additionally, bacteria have been reported to bind to the surface
of colonic epithelial cells and produce ligand mimetics that stimulate epithelial proliferation, contributing in neoplastic
cells to the hallmark capability for proliferative signaling. Beyond the gut, role of microbiota is considered important
also for oral cavity, lung, skin and cervical/vaginal cancers.
16
Usually, cancer tissue is considered as one made of “forever young” cells. Therefore, it seems surprising to see
“senescent cells” as a hallmark of cancer. Nevertheless, it was shown, that tumors keep the senescent cells alive. They
allow these cells to produce a host of cytokines, chemokines, proteases and other mediators which are typical for a
senescent cell - so-called senescence-associated secretory phenotype. It is considered to promote tumor phenotypes in
a paracrine fashion to viable cancer cells in proximity, as well as to other cells in the environment. Signaling molecules
(and proteases that activate and/or desequester them) convey hallmark capabilities. In different experimental systems,
senescent cancer cells have been shown to variously contribute to proliferative signaling, avoiding apoptosis, inducing
angiogenesis, stimulating invasion and metastasis, and suppressing tumor immunity.
Antitumor Effector Mechanisms

Cell-mediated immunity is the dominant antitumor mechanism.
• Cytotoxic T lymphocytes. CD8+ CTLs have a clear protective role against virus-associated neoplasms. Several studies
have shown that the number of tumor-infiltrating CD8+ T cells correlates with a better prognosis in a variety of
cancers, not only those caused by oncogenic viruses.
• NK cells. NK cells are capable of destroying tumor cells without prior sensitization and thus may provide the first line
of defense against tumor cells, including those which are nonimmunogenic for cytotoxic T cells.
• Macrophages. Activated macrophages exhibit cytotoxicity against tumor cells in vitro. T cells, NK cells, and
macrophages may collaborate in antitumor reactivity, because interferon-γ, a cytokine secreted by T cells and NK cells,
is a potent activator of macrophages. Activated macrophages may kill tumors by mechanisms similar to those used to
kill microbes.
Paraneoplastic syndromes
Paraneoplastic syndromes are clinical syndromes involving systemic effects that accompany cancer. They result from
substances produced by the tumor, and occur remotely from the tumor itself. Paraneoplastic syndromes may be the first or
most prominent manifestation of a cancer. When a patient without a known cancer presents with one of the “typical”
paraneoplastic syndromes, a diagnosis of cancer should be considered and investigated.
 Cachexia is a common finding in advanced cancers, and weight loss without dieting in an adult is a “red flag” for
malignancy. The exact cause for this is unknown, but increases in circulating factors such as tumor necrosis factor (TNF)
may play a role.
 Fever. Probably it is triggered by cytokines, released due to tumor associated inflammation.
 Endocrinopathies. Hypercalcemia is probably the most common one. Two general processes are involved in cancer-
associated hypercalcemia: (1) osteolysis induced by cancer, whether primary in bone, such as multiple myeloma, or
metastatic to bone from any primary lesion, and (2) the production of calcemic humoral substances by extraosseous
neoplasms. Only the second mechanism is considered to be paraneoplastic. The humoral factor that is most commonly
associated with paraneoplastic hypercalcemia is parathyroid hormone–related protein (PTHRP) that has partial structural
homology to parathyroid hormone (PTH). Some cancers (e.g. small cell carcinoma of lung) can cause Cushing syndrome
by excessive production of ACTH, while others cause hypoglycemia via insulin release.
 Neuromyopathic syndromes (peripheral neuropathies, encephalitis, myasthenic syndromes). The cause of these syndromes
is poorly understood, but appears to involve a cancer-induced immunologic attack on normal tissues. The initiating event
may be the ectopic expression of antigens that normally are restricted to the neuromuscular system by tumor cells. For
unknown reasons, the immune system recognizes these antigens as foreign and mounts a response that leads to tissue
damage.
 Hypercoagulability (migratory thrombophlebitis (Trousseau syndrome), disseminated intravascular coagulation,
17
nonbacterial thrombotic endocarditis) may be caused by tumor products
that activate clotting.
• Skin disorders. Acanthosis nigricans (Figure 13) is a disorder characterized
by gray black patches of thickened, hyperkeratotic skin with a velvety
appearance. It can be mediated by secretion of epidermal growth factor.
Figure 13․ Acanthosis nigricans.
18

10. Neoplasia GM Stom eng 2023

Uploaded by

Document Information

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

10. Neoplasia GM Stom eng 2023

Uploaded by

Copyright:

Available Formats

Department of Pathophysiology, Faculty of General Medicine and Stomatology, 2023

PATHOPHYSIOLOGY OF TUMOR GROWTH

Oncogenic virus Tumor caused by the virus Type of the virus

Proto-oncogenes, oncogenes, and oncoproteins

Figure 2. Growth factor signaling pathways in normal cell (left) and

Tumor Suppressor Genes

Figure 4. p53 is the guardian of the genome.

Figure 6․ Cancer cell avoids apoptosis by two major

Role of epigenetic alterations in carcinogenesis

Cellular and Molecular Hallmarks of Cancer

Figure 11. Invasion and metastasis.

Hallmarks of Cancer: New Dimensions

Antitumor Effector Mechanisms

Figure 13․ Acanthosis nigricans.

You might also like