Chapter 20 Omega

Cancer

A disease in which a clone of cells reproduces despite normal restraints and invades tissues.

Benign

A tumor that grows locally but does not invade surrounding tissue.

Malignant

A tumor that invades nearby tissue and can spread to distant sites.

Metastasis

The spread of cancer cells through blood or lymph to form secondary tumors.

Carcinoma

A cancer arising from epithelial cells.

Sarcoma

A cancer arising from connective tissue or muscle cells.

Leukemia

A cancer of blood-forming cells often producing abnormal white blood cells.

Lymphoma

A cancer originating from lymphoid (immune) cells.

Adenoma

A benign epithelial tumor with glandular organization.

Tumor (neoplasm)

A growth produced by excessive cell proliferation

Cancer as microevolution

Cancer develops through mutation, competition, and natural selection among somatic cells.

Clonal origin of cancer

Most cancers arise from a single abnormal cell that expands into a clone.

Somatic mutation

A DNA change in body cells passed to daughter cells that can contribute to cancer.

Carcinogenesis external agents

Cancer can result from chemical carcinogens or radiation that alter DNA.

Why cancer is relatively infrequent

Cancer requires multiple rare genetic changes, usually taking decades to accumulate.

Tumor progression timing

Cancers develop slowly because many sequential mutations are needed.

Natural selection in tumors

Mutant cells with growth advantages outcompete others, accelerating tumor evolution.

Genetic instability

Cancer cells often have high mutation rates and chromosomal abnormalities.

Aneuploidy

Gain or loss of whole chromosomes, common in cancer cells.

Chromothripsis

A catastrophic chromosome shattering and reassembly event causing massive genomic changes.

Cancer stem cells

A subpopulation of tumor cells capable of self-renewal and regenerating the tumor.

Six common hallmarks of cancer

Altered homeostasis, bypassing proliferation limits, evading apoptosis, altered metabolism, manipulating tissue/immune environment, and metastasis.

Altered homeostasis

Cancer cells divide faster than they die or avoid apoptosis, causing net growth.

Contact inhibition

Normal cells stop dividing when contacting neighbors

Replicative senescence

A limit to cell divisions due to telomere shortening

How tumor cells avoid senescence

They reactivate telomerase or use ALT to maintain telomeres.

Apoptosis evasion vs necrosis

Cancer cells block apoptosis but inner tumor cells often die from necrosis

Warburg effect

Cancer cells rely heavily on glycolysis and glucose uptake even with oxygen present.

Tumor stroma

Supportive connective tissue and cells surrounding the tumor that help its growth.

Tumor–stroma co-evolution

Cancer and stromal cells influence each other, promoting tumor survival and angiogenesis.

Angiogenesis

The formation of new blood vessels to supply the growing tumor.

Metastasis steps

Invasion, intravasation, circulation survival, extravasation, and colonization at a new site.

Why metastasis is rare

Few circulating tumor cells survive and successfully colonize distant tissues.

Oncogenes vs tumor suppressors

Oncogenes stimulate growth when activated

Retroviruses and oncogenes

Retroviruses can activate or introduce oncogenes that drive cancer.

Ras in cancer

Ras becomes oncogenic when mutations lock it in an active state, driving proliferation.

Ways proto-oncogene → oncogene

Point mutation, regulatory mutation, gene amplification, or chromosomal rearrangement.

Retinoblastoma (Rb) genetics

Loss of both Rb copies causes tumors

Ways to lose tumor-suppressor copy

Deletion, mutation, recombination, chromosome loss, or epigenetic silencing.

Cancer-critical genes

Genes whose mutation drives cancer development.

PI3K/Akt/mTOR pathway

A growth-promoting pathway often overactive in cancer.

PTEN

A phosphatase that inhibits PI3K signaling

p53 pathway

p53 activates repair, arrest, or apoptosis

Drivers vs passengers

Drivers directly promote cancer

Oncogene dependence

Some cancers rely on one key oncogene and respond to targeted therapy against it.

Cancer genome projects

Large sequencing efforts identify common mutations and drivers in cancers.

Epigenetic contributions

DNA methylation and histone changes can silence or activate cancer-related genes.

Aneuploidy prevalence

Most human cancers display characteristic chromosome-number abnormalities.

Drivers vs passengers

Driver mutations causally promote cancer growth and are recurrent across tumors, while passenger mutations are incidental byproducts of genomic instability

PI3K/Akt/mTOR pathway mutations

Activating mutations or loss of negative regulators (e.g., PTEN loss) hyperactivate PI3K→Akt→mTOR signaling, driving anabolic growth, increased glucose uptake and lipid/protein synthesis, and promoting tumor growth and the Warburg metabolic phenotype.

p53 activation and cancer

p53 is raised by DNA damage, telomere loss, hypoxia, oxidative/osmotic stress, and excessive oncogenic signaling (e.g., Myc)

Colorectal cancer — physiological progression

Normal epithelium → benign adenomatous polyps (adenomas) → accumulation of mutations and dysplasia → invasive carcinoma → possible metastasis

FAP (familial adenomatous polyposis) genetics

FAP is caused by inherited loss-of-function mutations in one APC allele (germline), leading to early, numerous colorectal polyps that acquire a second hit in APC in colon cells, driving near-certain progression to cancer if untreated.

HNPCC / Lynch syndrome genetics

HNPCC (Lynch) is due to inherited defects in DNA mismatch-repair genes (e.g., MLH1, MSH2), which greatly increase mutation rates when the remaining allele is lost, predisposing to colorectal cancer without massive polyposis and producing microsatellite instability.

Sequence of genetic changes in colorectal cancer

Commonly: early APC loss → expansion of abnormal crypt/stem cells → later activation of K-Ras in enlarging polyps → subsequent loss of p53 and other alterations → progression from adenoma to carcinoma (with variability across cases).

Small-molecule therapy for CML (Bcr-Abl inhibition)

CML is driven by the Bcr-Abl fusion tyrosine kinase (Philadelphia chromosome)

Directing the immune system to cancer

Strategies include monoclonal antibodies (blocking or toxin-conjugated), adoptive T-cell transfer/expansion, CAR-T cell engineering, and vaccines—these increase tumor antigen recognition and T-cell–mediated killing of cancer cells.

Removing tumor immunosuppression (checkpoint blockade) and risks

Checkpoint inhibitors (anti-PD-1/PD-L1, anti-CTLA-4) or blockade of tumor immunosuppressive signals can unleash T cells to kill tumors but may cause systemic immune hyperactivation and autoimmunity (severe inflammatory side effects).

Cancer stem cells

Some tumors contain a rare subpopulation of self-renewing cancer stem cells that generate most tumor cells (transit-amplifying progeny). They are often slowly dividing and can repopulate the tumor after treatment, making cure difficult because therapies that kill rapidly dividing cells may spare these stem cells.

Six hallmarks of cancer

The common hallmarks are: (1) altered homeostasis (growth > death), (2) bypass of proliferation limits, (3) evasion of cell-death signals, (4) altered metabolism, (5) manipulation of the tissue/immune environment, and (6) escape and metastasis.

Altered homeostasis (apoptosis vs division)

Cancer arises when cell division outpaces cell death—either by increased proliferation or by evading apoptosis—causing net tumor growth.

Contact inhibition

A normal process where cells stop dividing/moving when they touch neighbors

Replicative cell senescence

A permanent arrest of cell division after many population doublings (telomere shortening triggers DNA-damage signals), serving as a barrier to unlimited proliferation.

Why cells undergo senescence

Telomere erosion and resulting DNA-damage signals activate cell-cycle arrest to prevent genomic instability and malignant transformation.

How cancer cells avoid senescence

Most reactivate telomerase to maintain telomeres

Do tumor cells undergo apoptosis

Tumor cells commonly disable apoptosis pathways to survive stress, but many cells within large tumors still die by necrosis due to hypoxia and nutrient shortage

Warburg effect

Tumor cells take up large amounts of glucose and favor aerobic glycolysis (producing building blocks for growth) even when oxygen is present, supporting rapid proliferation and enabling glucose-based imaging.

Tumor stroma

The supportive connective tissue around a tumor (fibroblasts, immune cells, endothelial cells, extracellular matrix) that provides structural support and signals the cancer needs to grow.

Tumor–stroma co-evolution

Cancer cells secrete signals and proteases that remodel stroma

Angiogenesis in tumors

Tumors induce formation of new blood vessels to supply oxygen and nutrients as they grow, often via stromal signaling.

Process of metastasis

Steps: local invasion → intravasation into lymph/blood → survival in circulation → extravasation into distant tissue → colonization and proliferation to form a secondary tumor.

Why metastasis is rare

Although many cells enter circulation, very few survive, adapt to foreign microenvironments, and successfully colonize—colonization is the rate-limiting, low-probability step.

Oncogenes vs tumor suppressors

Oncogenes result from gain-of-function changes (act dominantly) that promote growth

Gain-of-function vs loss-of-function

Gain-of-function mutations (oncogenes) typically require only one altered allele to drive cancer

How retroviruses cause cancer

Retroviruses can insert into the host genome, activate nearby cellular proto-oncogenes, or carry captured viral oncogenes (v-onc) that are mutated versions of host proto-oncogenes, driving transformation.

Ras in cancer

Ras proteins are GTPases that relay growth signals

Ways proto-oncogene → oncogene

Point or regulatory mutations, gene amplification (extra copies), chromosomal rearrangements that create fusion proteins or place genes under strong promoters, and deletions that produce constitutive activity.

Example of receptor activation

Deletion or mutation of extracellular domains (eg. in some EGF receptor mutants) can make receptors constitutively active without ligand, driving proliferation.

Retinoblastoma genetics

Retinoblastoma arises from loss of Rb tumor-suppressor function (a loss-of-function mutation). Hereditary cases inherit one defective Rb allele and often develop bilateral/multiple tumors

Two-hit model for tumor suppressors

Tumor suppressor inactivation typically follows two events: one allele lost/inactivated first (sometimes inherited) and the second allele lost later somatically, eliminating gene function.

Ways to lose the wildtype tumor-suppressor copy

Small deletions, point mutations, mitotic recombination/gene conversion, chromosome loss, large rearrangements, or epigenetic silencing (promoter methylation).

Genetic vs epigenetic inactivation

Genetic changes alter DNA sequence (deletions, mutations, LOH)

Cancer-critical genes

Genes whose alteration drives cancer progression (drivers) as opposed to incidental passenger mutations

Genome disruption in cancer

Many cancers show gross genomic disorder—point mutations, copy-number changes, chromosomal rearrangements, aneuploidy, and catastrophic events like chromothripsis—contributing to heterogeneity.

Epigenetic contributions to cancer

Aberrant DNA methylation and histone modifications can silence tumor suppressors or alter gene networks