Week 1 – Introduction + Cancer Genome Mutations vs. Repairs

A comprehensive set of flashcards covering cancer biology topics from the lecture notes.

What is cancer?

A group of more than 200 diseases characterized by unregulated cell growth, driven by mutations and transformations resulting in the gains or losses of function.

What processes enable cancer cells to spread?

Invasion, angiogenesis, and metastasis.

What is carcinogenesis?

Transformation of a normal cell into a cancerous cell.

What are the lifetime cancer risk estimates for men and women?

Men about 40%; women about 39%.

What is the approximate death burden from cancer in Americans?

About 1 in 5 Americans.

Carcinomas account for roughly what percentage of cancers?

About 85%.

From what tissue are carcinomas derived?

Epithelium.

What are squamous carcinomas?

Carcinomas derived from flat protective squamous cells that line organs and body cavities (e.g., some skin, cervical, and lung cancers).

What are adenocarcinomas?

Carcinomas derived from glandular cells that produce mucin or are ciliated (e.g., thyroid, breast, endometrium, some respiratory cancers).

What are sarcomas derived from?

Mesodermal cells (bone, muscle, connective tissue).

What are the classic hallmarks of cancer?

Sustaining proliferative signaling, evading growth suppressors, enabling replicative immortality, inducing or accessing vasculature, activating invasion & metastasis, resisting cell death, avoiding immune destruction, tumor-promoting inflammation, genome instability & mutation, and deregulating cellular metabolism.

What are the emerging hallmarks of cancer?

Unlocking phenotypic plasticity, nonmutational epigenetic reprogramming, polymorphic microbiomes, and senescent cells.

How can aqcuired mutations disrupt or alter growth factor pathways?

Self-sustained signaling, expression of receptors, deregulation of signaling pathways, microenvironment conditions, neovascularization.

What does self-sustained signaling refer to in cancer biology?

Cancer cells ability secrete and sense growth factors.

How can signaling pathways become deregulated in cancer?

Mutations in genes activate protein kinases, which impact signaling and alter growth.

What is neovascularization?

The growth of new blood vessels to supply a tumor.

What is replicative immortality in cancer?

The ability to divide indefinitely by maintaining telomere length, often via telomerase.

What happens to telomeres during normal cell replication?

Telomeres shorten with each round of DNA replication, leading to senescence.

How do cancer cells achieve unlimited proliferative potential via telomeres?

They maintain telomere length through altered telomere maintenance (e.g., telomerase activation).

What is resisting cell death in cancer?

Alterations to apoptotic pathways and related proteins that prevent cell death.

How can cancer cells evade cytotoxicity through autophagic pathways during cell stress?

Cancer stem cells can impersonate other cell types, alter cell receptor expression to evade NK cell detection

What is genome instability in cancer?

Mutations can occur anywhere, including regulatory regions, which can drive gene activation or overexpression.

Which of the cancer hallmarks does genome instability and mutation establish?

Sustained proliferative signaling, evading growth suppressors, replicative immortality, resisting cell death, and metastasis.

What is an oncogene?

A gene that promotes overproduction or increased activity of a protein product that initiates tumor formation; gain-of-function mutations; dominant manner; a single mutated allele is suffcient for an effect.

What is a tumor suppressor gene?

A gene that causes loss-of-function mutations and permits growth; recessive manner; typically requires both alleles to be mutated for an effect.

What is haploinsufficiency?

One mutated allele yields insufficient protein to suppress tumor formation; can occur for DNA repair genes.

What factors influence carcinogenesis?

Aging, environment, reproductive life, diet/exercise, alcohol, and smoking.

What DNA-damaging factor is associated with UV radiation?

Formation of thymine dimers leading to mutations.

What are PFAs and why are they relevant to cancer?

Per- and polyfluoroalkyl substances are man-made chemicals widely used in industry and consumer products since the 40s (e.g., stain repellants, non-stick coatings, and flame/water resistance). Lifetime exposure can lead to decreased birth weight and increased risk of cancer (e.g., kidney and liver)

How do PFAs persist environmentally?

Via movement through the water cycle.

Which viruses are linked to cancer in these notes?

Human papillomavirus (HPV) – cervical cancer; Human herpesvirus 8 (HHV-8) – Kaposi’s sarcoma.

What protective reproductive/hormonal factors are mentioned for breast cancer risk?

Having children at a young age; giving birth to 2+ children; late start to menstruation; early start to menopause (risk for some cancers); not using hormonal contraception; not using hormone replacement therapy.

What lifestyle factor can reduce cancer risk by about 25%?

Regular physical activity as it improves function of the immune system toward cancer cells.

Diets high in what compounds may reduce cancer risks?

Polyphenols and carotenoids

How do alcohol and smoking influence cancer risk?

Alcohol increases risk for several cancers; smoking accounts for ~40% of cancer deaths; they have a synergistic effect when combined.

Which types of cancer is smoking primarily involved with?

Lung, pancreas, bladder, kidney, mouth, stomach, and liver.

Chronic alcohol use increases risk for which 7 cancers (at the least)?

Mouth, throat, larynx, esophagus, breast, liver, and colon/rectum.

What do protein kinases do?

Protein kinases add a phosphate group to a hydroxyl group on specific amino acids, resulting in a conformational change that can regulate protein activity.

Where can protein kinases be found?

At the cell surface as transmembrane receptors, inside the cell as intracellular transducers, and inside the nucleus.

What three processes do protein kinases play a critical role in?

Cell cycle progression, signal transduction, and transcription.

What is the role of protein kinases in cancer therapy?

Protein kinases regulate signaling pathways; are important targets for cancer drugs.

What are RAS proteins and their significance in cancer?

G proteins that act as intracellular transducers of signal for growth; mutations keep RAS in the ON (GTP-bound) state, driving persistent proliferation; mutated in over 50% of some cancers (e.g., colon)

What is TP53 (p53) and its role in cancer biology?

A tumor suppressor that guards genome integrity and coordinates stress responses by inducing apoptosis when necessary; mutated in >50% of cancers.

What is RB1 and its role in cancer biology?

Retinoblastoma gene; a tumor suppressor central to cell cycle control via its inhibition of cell proliferation.

What is cancer genomics?

Study of DNA sequence and gene expression differences between normal and cancer cells using sequencing to guide targeted therapies.

What are The Cancer Genome Atlas (TCGA) and Global Cancer Observatory?

Large data programs that generate and share cancer genomics data to support research and surveillance.

What is the difference between benign and malignant tumors?

Benign tumors are encapsulated and non-metastatic; malignant tumors invade and metastasize.

What is carcinoma in situ?

A cancer that is contained and not yet metastasized, analogous to dysplasia; can progress to invasive cancer.

What is the tumor microenvironment (TME)?

The ecosystem of cells, molecules, and blood vessels surrounding and nourishing a tumor, with ongoing interactions.

What is tumor-promoting inflammation in cancer biology?

Nitric oxide (NO) from the TME activates macrophages, increasing pro-inflammatory cytokines and altering immune responses.

What is the SASP?

Senescence-associated secretory phenotype: release of chemokines, cytokines, and proteases by senescent cells.

What is metabolic reprogramming in cancer?

Cancer cells alter carbohydrate, lipid, and protein metabolism to meet growth needs; influenced by the TME.

What is cellular senescence role in cancer?

Senescence stops proliferation but has been shown to promote tumor growth in certain cancers/situations by inducing proliferative growth, allowing cells to transiently move from senescent to non-senescent states.

What is phenotypic plasticity in cancer cells?

Disruptions of differentiation, including dedifferentiation, blocked (terminal) differentiation, and transdifferentiation.

What is dedifferentiation?

Mature cells reverting to a progenitor-like state.

What is transdifferentiation (metaplasia)?

Conversion of a cell type into a different lineage.

What is nonmutational epigenetic reprogramming?

Epigenetic changes that promote the selective advantage of hallmark capabilities and clonal outgrowth of cancer cells without DNA sequence changes.

What is epigenetic regulatory heterogeneity?

Existence of multiple subpopulations within a tumor with distinct epigenetic states; very problematic

What is anchorage independence?

Cancer cells can grow without being attached to a substrate, unlike normal cells.

What is contact inhibition and how do cancer cells differ?

Normal cells stop growing when they touch; cancer cells lack this inhibition and pile up.

What are the 'Molecules of Fame' in cancer biology?

Protein kinases, RAS proteins, TP53, and RB1.

Why is cancer genomics important for precision medicine?

Characterizing DNA and expression differences enables targeted drug design and personalized therapy.

What is cytostatic chemotherapy?

A treatment that prevents proliferation of cancer cells.

What is cytotoxic chemotherapy?

A treatment that causes severe DNA damage triggering apoptosis in rapidly dividing cells.

How do conventional chemotherapies disrupt the cell cycle, and what are the pros and cons of their mechanism?

Conventional chemotherapies disrupt the cell cycle by targeting DNA, RNA, and proteins. This allows for broad specificity, meaning all rapidly dividing cells are killed, healthy or not.

What is therapeutic index?

The value of the difference between the minimum effective dose and the maximum tolerated does (MTD); The larger the value, the safer the drug; Most chemotherapies have a very narrow therapeutic index.

Describe Phase I of a clinical trial.

20-100 patients are enrolled to examine dose responses for the assessment of drug safety.

Describe Phase II of a clinical trial.

10s-100s of patients enrolled to examine efficacy and side effects.

Describe Phase III of a clinical trial.

100s-1000s of patients enrolled to confirm drug effectiveness, monitor side effects, and compare efficacy of the new drug to conventional treatments.

What percentage of tested drugs pass all three phases of clinical trials and are marketed clinically?

30%

What is angiogenesis?

The process through which new blood vessels form from existing ones. These new blood vessels are immature, poorly formed, disorganized, and leaky, allowing cancer cells to easily escape.

What is the angiogenic switch?

A shift in the balance between the activities of angiogenesis inhibitors and activators allows solid tumors to sustain their growth beyond 2-3 mm in diameter and become malignant.

What are the six steps of cancer metastasis?

Local invasion, intravasation, transport, extravasation, formation of micrometastasis, and colonization.

What happens during the “local invasion” step of cancer metastasis?

The small in situ tumor breaks through the basement membrane barrier.

What happens during the “intravasation” step of cancer metastasis?

Tumor cells move through the walls of the capillaries or lymphatics into the circulatory system; a critical step in this pathway and involves a complex, morphological change, wherein the cancer cell acquires properties of invasiveness and cell motility, enabling it to push its way through the capillary wall into the circulatory system.

What happens during the “transport” step of cancer metastasis?

Cancer cells travel through blood or lymph until they anchor to a solid supporting tissue; most cancer cells can be lost or destroyed due to hostile conditions; surviving cancer cells get lodged in the first set of capillaries they encounter (due to large cells blocking the small passage of the capillaries) and form microthrombi.

What happens during the “extravasation” step of cancer metastasis?

Cancer cells move into the tissues they are lodged in, typically lungs, brain or liver; cancer cells in microthrombi now push through capillary wall and into the tissue microenvironment

What happens during the “formation of micrometastasis” step of cancer metastasis?

Cancer cells are now able to reactivate the cell proliferation pathways and form a small tumor mass which either develops in the lumen of the capillary or through the vessel wall.

Why is the “colonization” step of cancer metastasis the most complex?

Because the new environment may not always provide the necessary survival and proliferation factors needed for growth; most cancer cells usually die or survive for long periods as micrometastases (much harder to detect).