Neoplasia

• Nomenclature
• Epidemiology
• Cancer genes
• Genetic lesions in cancer
• Carcinogenesis; a multistep process
• Hallmarks of cancer
• Etiology of cancer: carcinogenic agents
• Clinical aspects of neoplasia
Characteristics of benign and malignant tumors

• Benign and malignant tumors are distinguished based on

differentiation, local invasiveness, and distant spread.
• In general, benign tumors resemble the tissue of origin, are well
differentiated, are well circumscribed, have a capsule, and
remain localized.
• In general, malignant tumors are poorly or completely
undifferentiated (anaplastic), often (but not always) grow rapidly,
are poorly circumscribed, invade surrounding normal tissues,
and have the ability to metastasize to distant sites.
Epidemiology of Cancer

• Cancer incidence varies with age, geographic factors, and

genetic background; it is most frequent in older adults, but
certain types characteristically occur in children.
• Geographic variation in cancer incidence results mostly from
different environmental exposures, such as infectious
agents, smoking, alcohol, diet, obesity, reproductive history,
and exposure to carcinogens.
• Cancer risk rises in the setting of chronic inflammation or
excessive hormonal stimulation.
• Epithelial cell linings of tissues may develop morphologic
changes (dysplasia) that signify an increased risk for
developing cancer.
• Cancer risk is modified by interactions between
environmental exposures and genetic variants.
Genetic lesions in cancer - 1

• Mutations belong to two major classes, driver (pathogenic) and

passenger (neutral).
• Passenger mutations may become driver mutations if selective
pressure changes (e.g., under drug treatment).
• Tumor cells may acquire driver mutations through point
mutations and nonrandom chromosomal abnormalities (gene
rearrangements, deletions, and amplifications).
Genetic lesions in cancer - 2

• Gene rearrangements often lead to overexpression of oncogenes

or generation of novel fusion proteins, whereas gene
amplifications usually increase the expression of oncogenes and
deletions cause the loss of tumor suppressor genes.
• Overexpression of miRNAs can reduce expression of tumor
suppressors and loss of expression of miRNAs can lead to
overexpression of oncogenes.
• Tumor suppressor genes and DNA repair genes may also be
silenced by epigenetic changes.
 Amplification of
the NMYC gene in
human
neuroblastoma.
Self-Sufficiency in Growth Signals

• Proto-oncogenes are normal cellular genes whose products

stimulate cell proliferation.
• Oncogenes are mutant or overexpressed versions of proto-
oncogenes that produce inappropriate growth-promoting
signals.
Oncoproteins

• Oncoproteins drive uncontrolled cell proliferation by several

mechanisms, including autocrine signaling by secreted
factors (e.g., PDGF in brain tumors); constitutive activity of
proteins involved in progrowth signaling pathways
(e.g., HER2 in breast cancer; BCR-ABL in leukemia; and
RAS, in many cancers); excessive activity of transcription
factors that turn on a program of gene expression that
promotes cell growth (e.g., MYC, in many cancers); and
constitutive expression of proteins that directly regulate cell
cycle progression (e.g., cyclin D, in diverse cancers).
Model for action
of RAS genes
RB: Governor of the Cell Cycle - 1

• Like other tumor suppressors, both copies of RB must be

dysfunctional for tumorigenesis to occur.
• In familial retinoblastoma, one defective copy of the RB gene
is present in the germline.
• RB inhibits G1-to-S transition of cells by binding to E2F
transcription factors.
• RB is negatively regulated by growth factor signaling, which
leads to activation of cyclin D–CDK4/6 complexes,
inactivation of RB by phosphorylation, and release of E2F
factors.
RB: Governor of the Cell Cycle - 2

• Almost all cancers have a disabled G1 checkpoint due to

mutation of RB or genes that regulate RB (e.g., genes
encoding cyclin D, CDK4, and CDK inhibitors).
• Several oncogenic DNA viruses (e.g., HPV) encode proteins
that bind and inhibit RB.
TP53 Gene; guardian of the genome

• TP53 encodes p53, a central monitor of stress in the cell.

• DNA damage leads to phosphorylation and activation of p53,
which upregulates factors such as p21 that sustain the activity
of RB and cause a G1-S block in the cell cycle.
• If DNA damage cannot be repaired, p53 turns on additional
genes that induce cellular senescence or apoptosis.
• The majority of human cancers demonstrate biallelic mutations
in TP53.
• Patients with Li-Fraumeni syndrome inherit one defective copy
of TP53 in the germline and develop a wide variety of tumors.
• p53 is inhibited by proteins encoded by oncogenic DNA viruses
(e.g., HPV).
TGF-β, Contact Inhibition

• TGF-β inhibits proliferation by activating growth-inhibiting

genes (e.g., genes encoding cyclin-dependent kinase
inhibitors) and suppressing growth-promoting genes
(e.g., MYC).
• TGF-β pathway components are frequently compromised by
mutations in many tumors, including pancreatic, colorectal,
gastric, and esophageal carcinomas.
• E-cadherin maintains contact inhibition, which is lost in
malignant cells.
APC-β-Catenin Pathways

• APC blocks proliferation of colonic epithelial cells by

enhancing the destruction of β-catenin, a transcription factor
in the WNT signaling pathway.
• With the loss of APC, β-catenin is stabilized, translocates to
the nucleus, and upregulates progrowth genes (e.g., MYC).
• Familial adenomatous polyposis syndrome is caused by
germline mutations in APC and is associated with the
development of hundreds of colonic polyps and eventually
colon carcinoma.
Altered Cellular Metabolism -1

• Warburg metabolism favors glycolysis over oxidative

phosphorylation. It is induced in normal cells by exposure to
growth factors and becomes fixed in cancer cells due to the
action of certain driver mutations.
• Many oncoproteins (e.g., RAS, MYC, mutated growth factor
receptors) induce Warburg metabolism to provide cellular
building blocks needed for prolieration, and many tumor
suppressors (e.g., PTEN, NF1, p53) oppose it.
Altered Cellular Metabolism - 2

• Stress may induce cells to consume their components in a

process called autophagy, which is a double-edged sword in
cancers, as cancer cells may accumulate mutations to avoid
autophagy yet also use autophagy to provide nutrients for growth
and survival.
• Some oncoproteins (e.g., mutated IDH) are enzymes that
catalyze the formation of “oncometabolites” that alter the
epigenome, leading to oncogenic changes in gene expression.
Evasion of Apoptosis

• Evasion of cell death mainly involves acquired abnormalities

that interfere with the intrinsic (mitochondrial) pathway of
apoptosis.
• Evasion often involves loss of p53 (a proapoptotic transcription
factor) or overexpression of p53 inhibitors (e.g., MDM2).
• Other evasion mechanisms involve overexpression of
antiapoptotic members of the BCL2 family (e.g., BCL2, BCL-XL).
• In follicular lymphoma, BCL2 is overexpressed because of a
(14;18) translocation that fuses BCL2 with regulatory elements of
the immunoglobulin heavy chain gene.
• MDM2 inhibitors (which lead to activation of p53) and BCL2
family member inhibitors stimulate apoptosis through the intrinsic
pathway.
Limitless replicative potential (immortality)

• Normal cells lack telomerase, leading to telomere shortening,

activation of cell cycle checkpoints, and senescence.
• In cells with disabled checkpoints, DNA repair pathways are
activated by shortened telomeres, leading to chromosomal
instability and mitotic crisis.
• Tumor cells reactivate telomerase, staving off mitotic
catastrophe and achieving immortality.
Development of sustained angiogenesis

• Vascularization of tumors is essential for their growth and is

controlled by the balance between angiogenic and antiangiogenic
factors that are produced by tumor and stromal cells.
• Hypoxia triggers angiogenesis through the actions of HIF- 1α on
the transcription of the pro-angiogenic factor VEGF. Because of
its ability to degrade HIF-1α and thereby prevent angiogenesis,
VHL acts as a tumor suppressor. Inheritance of germ line
mutations of VHL causes VHL syndrome, characterized by the
development of a variety of tumors.
• Many other factors regulate angiogenesis; for example, p53
induces synthesis of the angiogenesis inhibitor TSP-1.
Sustained Angiogenesis

• Vascularization of tumors is essential for their growth.

• Angiogenesis is controlled by a balance between angiogenic
and antiangiogenic factors.
• Hypoxia triggers angiogenesis by stabilizing HIF-1α, leading
to upregulation of VEGF, a key growth factor for endothelial
cells.
• Many factors regulate angiogenesis, including p53, which
induces synthesis of the angiogenesis inhibitor
thrombospondin-1, and RAS, MYC, and MAPK, which
upregulate VEGF expression.
• VEGF inhibitors slow the growth of advanced cancers but
are not curative.
Invasion and Metastasis
• Invasion of tissues, a hallmark of malignancy, occurs in four
steps: (1) loosening of cell–cell contacts; (2) degradation of
ECM; (3) attachment to ECM components; and (4) migration of
tumor cells.
• Cell–cell contacts are weakened due to loss of E-cadherin.
• Basement membrane and interstitial matrix degradation is
mediated by proteolytic enzymes secreted by tumor cells and
stromal cells (e.g., MMPs and cathepsins).
• Proteolytic enzymes also release growth factors from ECM and
generate chemotactic and angiogenic fragments.
• Many tumors arrest in the first capillary bed they encounter (lung
and liver, most commonly).
• Other tumors show marked organ tropism that is not explained
by anatomy
 The metastatic cascade. Schematic
illustration
of the sequential steps involved in the
hematogenous spread of a tumor.

© 2005 Elsevier
Evasion of Immune Surveillance - basic

• Tumor cells can be recognized by the immune system as

nonself and destroyed.
• Antitumor activity is mediated by predominantly cell-
mediated mechanisms.
• Tumor antigens are presented on the cell surface by MHC
class I molecules and are recognized by CD8+ CTLs.
• Tumor antigens include products of mutated genes,
overexpressed or aberrantly expressed proteins, and tumor
antigens produced by oncogenic viruses.
Evasion of Immune Surveillance – clinical relevance

• Patients who are immunosuppressed have an increased risk

for cancer, particularly types caused by oncogenic DNA
viruses.
• In immunocompetent patients, tumors may avoid the immune
system by several mechanisms, including selective
outgrowth of antigen-negative variants, loss or reduced
expression of histocompatibility molecules, and
immunosuppression due to expression of certain factors
(e.g., TGF-β, PD-1 ligands) by the tumor cells.
• Antibodies that block some of these mechanisms are used to
treat patients with advanced cancers.
Genomic Instability as an Enabler of Malignancy - 1

• Inherited mutations in DNA repair genes are associated with

increased cancer risk.
• Hereditary nonpolyposis colorectal cancer (Lynch syndrome) is
caused by defects in the mismatch repair system that lead to
instability of short DNA repeat regions called microsatellites and
the development of several tumors, particularly colon cancer.
• Xeroderma pigmentosum is caused by a defect in nucleotide
excision repair that leads to a failure to repair DNA damage caused
by UV light and development of skin cancers in sites exposed to
sunlight.
Genomic Instability as an Enabler of Malignancy - 2

• Other syndromes are caused by defects in the homologous

recombination DNA repair; these defects variously lead to Bloom
syndrome, ataxia-telangiectasia, Fanconi anemia, and hereditary
breast/ovarian cancer.
• Familial breast/ovarian cancer syndrome is most often caused by
mutations in the genes encoding the DNA repair factors BRCA1
and BRCA2.
• Intrinsic genomic instability in lymphocytes undergoing antigen
receptor gene rearrangement/mutation may lead to mutations that
result in lymphoid neoplasms.
Therapeutic targeting of the hallmarks of cancer
Chemical and Radiation Carcinogenesis - 1

• Chemical carcinogens have highly reactive electrophile

groups that damage DNA.
• Carcinogens include direct-acting agents (e.g., alkylating
agents used as chemotherapy) that do not require metabolic
conversion to become carcinogenic and indirect-acting
agents (e.g., benzo[a]-pyrene, azo dyes, aflatoxin) that are
not active until converted to an ultimate carcinogen by
endogenous metabolic pathways.
Chemical and Radiation Carcinogenesis - 2

• Tumor promoters act by stimulating the proliferation of cells

exposed to carcinogens either directly or indirectly, the latter
through tissue injury and associated regenerative repair.
• Ionizing radiation causes mutations that may affect cancer
genes, thereby driving carcinogenesis.
• UV rays in sunlight induce the formation of pyrimidine dimers
within DNA, leading to mutations due to error-prone repair.
Infections Associated With Cancer - 1

• HPV is associated with benign warts and cervical cancer.

• Oncogenic strains of HPV encode two viral oncoproteins, E6
and E7, that inhibit p53 and RB, respectively.
• EBV is implicated in the pathogenesis of diverse lymphomas
(e.g., Burkitt lymphoma), nasopharyngeal carcinoma, a
subset of gastric carcinoma, and rarely smooth muscle
tumors.
• Certain EBV gene products contribute to oncogenesis by
stimulating normal B-cell proliferation pathways.
• Compromise of T-cell function often leads to EBV-driven B-
cell lymphomas.
HPV Carcinogenesis
EBV carcinogenesis
Infections Associated With Cancer - 2

• Chronic HBV and HCV infection is associated with 70% to

85% of hepatocellular carcinomas worldwide, which appear
to be caused largely by chronic inflammation and ongoing
repair of the liver.
• H. pylori infection is implicated in both gastric
adenocarcinoma and B-cell lymphomas known as extranodal
marginal zone lymphomas.
• Development of gastric carcinoma involves chronic
inflammation and gastric epithelial cell regeneration.
• Development of B-cell lymphoma involves an initial reactive
polyclonal proliferation of B-cells that are susceptible to
acquiring mutations that lead to clonal B-cell outgrowth
(transformation).
Clinical aspects of tumors

• Cachexia is a common complication of advanced cancer that

is defined by the progressive loss of body fat and lean body
mass and accompanied by profound weakness, anorexia,
and anemia.
• Cachexia is caused by release of cytokines by the tumor or
host.
Clinical aspects of tumors – paraneoplastic syndromes

• Paraneoplastic syndromes are defined by the presence of

symptoms that are not explained by tumor spread or by
release of hormones appropriate to the tissue.
• Paraneoplastic syndromes are caused by the ectopic
production and secretion of bioactive substances
(e.g., ACTH, PTHrP, or TGF-α) by tumor cells.
Clinical aspects of tumors – grading and staging

• Tumor grading is determined by cytologic appearance and is

based on the idea that behavior and differentiation are
related (poorly differentiated = aggressive behavior).
• Tumor staging (extent of tumor) is determined by surgical
exploration or imaging and is based on tumor size, local and
regional lymph node spread, and distant metastases.
• Staging is of greater clinical value than grading.
Laboratory diagnosis of cancer
• Several sampling approaches exist for tumors (e.g., excision,
biopsy, fine-needle aspiration, cytologic smears).
• Testing modalities include immunohistochemistry and flow
cytometry (used to identify protein expression patterns that define
different entities); serum markers (e.g., PSA), used to screen
populations for cancer and to monitor for recurrence
after treatment; and molecular profiling (e.g., DNA or RNA
sequencing).
• Molecular profiling is used to determine diagnosis and prognosis;
identify therapeutic targets; detect minimal residual disease after
therapy; diagnose patients with a hereditary predisposition to
cancer; and characterize circulating tumor cells and DNA shed
into blood, stool, sputum, and urine (liquid biopsies).
Diverse tumor types that share a common mutation, BRAF
(V600E), may be candidates for treatments with the same drug