CPAT3201 - Lectures 21-26

What is neoplasia?

refers to abnormal and uncontrolled cell proliferation forming a tumour (it means "new growth")

What is a tumour?

a swelling or mass caused by abnormal cell growth

What is a benign tumour?

a neoplastic growth that remains localised and does not invade surrounding tissues

What is a malignant tumour?

malignant tumour invades surrounding tissues and can spread to distant sites (metastasis)

What does the term "cancer" refer to?

a generic term for malignant tumours (derived from the Greek word "karkinos," meaning crab)

What are the basic components of tumours?

parenchyma (neoplastic cells determining tumour behaviour) and stroma (non-neoplastic supporting tissue)

How are benign tumours usually named?

benign tumours are generally named with the suffix "-oma" attached to the cell type of origin (e.g., adenoma, lipoma).

Give examples of benign tumours and their cell types.

adenoma (glandular tissue), lipoma (adipose tissue), schwannoma (Schwann cells), chondroma (cartilage)

What is metaplasia?

the reversible replacement of one adult cell type by another, often in response to chronic injury

What is dysplasia?

disordered epithelial growth that may progress to cancer but can also regress if the stimulus is removed

What is anaplasia?

a lack of differentiation where tumour cells lose normal structure and function, showing pleomorphism and abnormal mitoses

What are the four main processes distinguishing benign from malignant tumours?

differentiation and anaplasia, rate of growth, local invasion, and metastasis

Describe the growth and invasion characteristics of benign tumours.

they grow slowly, are well-circumscribed, often encapsulated, and do not invade adjacent tissues

Describe the growth and invasion characteristics of malignant tumours.

they grow rapidly, are poorly circumscribed with irregular margins, invade local tissues, and metastasise

What is the hallmark microscopic difference between benign and malignant tumours?

benign tumours have organized, well-differentiated cells; malignant tumours show disorganized, poorly differentiated or anaplastic cells

How does tumour differentiation affect prognosis?

well-differentiated tumours generally have a better prognosis; poorly differentiated or anaplastic tumours tend to be more aggressive

What is desmoplasia?

desmoplasia is the fibrous tissue response around malignant tumours, often seen as dense collagenous stroma

What is metastasis?

the spread of cancer cells from the primary tumour to distant organs, indicating malignancy

What are the three main pathways of metastasis?

lymphatic spread, haematogenous (blood) spread, and transcoelomic (across body cavities) spread

Which cancers primarily spread via the lymphatic system?

carcinomas commonly spread via lymphatic metastasis

What is haematogenous metastasis and which tumours commonly use this pathway?

involves tumour cells entering blood vessels and spreading, typical of sarcomas

What is transcoelomic spread?

tumour cell seeding across body cavities like the peritoneal, pleural, or cerebrospinal fluid spaces

What is the invasion-metastasis cascade?

a sequential process involving local invasion, intravasation, transit through vessels, extravasation, micrometastasis formation, and macroscopic tumour growth

What happens during Phase 1 of the invasion-metastasis cascade (ECM invasion)?

tumour cells loosen adhesion, degrade basement membrane, lose attachment to ECM, and migrate

What is the role of cadherins and catenins in tumour invasion?

they mediate cell-cell adhesion; their downregulation or mutation facilitates tumour cell detachment

What challenges do tumour cells face during vascular dissemination?

tumour cells face shear stress, apoptosis, and immune attacks but may evade destruction by forming aggregates with platelets

What is the clonal theory of metastasis?

malignant tumours evolve subclones with progressively greater metastatic potential

What are the main categories of cancer risk factors?

behavioral (e.g., smoking, diet), biomedical (e.g., diabetes, obesity), environmental (e.g., pollutants, UV exposure)

What is DALY?

Disability-adjusted life years (DALY) - measure the total years of healthy life lost due to disease (both premature death and disability)

What cancer risk factor contributes most to the cancer burden?

tobacco use, accounting for about 22% of cancer burden

How does age relate to cancer incidence?

it increases with age due to cumulative mutations and reduced immune surveillance

Give examples of acquired pre-neoplastic lesions.

cervical dysplasia, cirrhosis, solar keratosis, and ulcerative colitis, which predispose to cervical, liver, skin, and colon cancers respectively

How do geographic variables affect cancer rates?

cancer incidence and mortality vary widely by region due to genetic, environmental, and lifestyle differences

What is the most common cancer associated with ionizing radiation?

leukemia

What cancer is commonly seen in children exposed to radiation, e.g., post-Chernobyl?

thyroid cancer

How does UV radiation cause cancer?

by forming pyrimidine dimers, damaging DNA → skin cancers

What type of exposure is associated with melanoma?

intermittent intense UV exposure

Name a direct-acting chemical carcinogen.

cyclophosphamide (alkylating agent)

Name an indirect-acting chemical carcinogen and the cancer it causes.

Benzo[a]pyrene → lung cancer

What cancer is associated with aflatoxin B1 exposure?

hepatocellular carcinoma

What virus causes cervical cancer and which strains are high risk?

HPV, types 16 & 18

What oncoproteins do high-risk HPVs express?

E6 (inactivates p53) and E7 (inactivates Rb)

What virus is associated with Burkitt lymphoma?

Epstein-Barr Virus (EBV)

Which RNA virus is oncogenic in humans?

HTLV-1 (causes T-cell leukemia/lymphoma)

What is cancer cachexia?

Wasting syndrome: loss of fat and muscle, driven by cytokines (e.g., TNF)

What are paraneoplastic syndromes?

symptoms not explained by tumour location/hormones (e.g., SIADH, hypercalcemia)

Name three population-based cancer screening programs.

Breast screening (mammography), Cervical screening (HPV test), Bowel screening (FOBT)

What is the "triple assessment" in breast cancer diagnosis?

Clinical exam + imaging (e.g., mammogram) + biopsy

What test replaced Pap smears for cervical screening?

HPV PCR testing

What tumour marker is associated with prostate cancer?

Prostate Specific Antigen (PSA)

What does alpha-fetoprotein indicate?

Hepatocellular carcinoma

What is a proto-oncogene?

a normal gene that promotes cell growth

What is an oncogene?

a mutated proto-oncogene that causes uncontrolled growth

What is an oncoprotein?

a protein produced by an oncogene that drives cancer

What is the Vogelstein cascade?

a model of stepwise mutations in colorectal cancer from adenoma to carcinoma

How does EGFR mutation lead to cancer?

causes constitutive receptor activation → MAPK & PI3K-AKT pathways → proliferation

What is the most common Ras mutation in cancer?

G12V or G12R → impairs GTPase activity → constant Ras activation

What is the BRAF V600E mutation?

substitution that makes BRAF constitutively active → seen in melanomas

What does MYC overexpression cause?

increased transcription of growth-promoting genes

What cancer has MYC translocation?

Burkitt lymphoma → t(8;14)

What checkpoint is commonly disrupted in cancer?

G1/S checkpoint (It monitors for DNA damage, such as breaks or mutations. If damage is detected, the checkpoint halts cell cycle progression.)

What cyclin/CDK changes are common in cancer?

Cyclin D amplification, CDK4 amplification, p16 deletion

What is the use of molecular profiling in cancer?

identifies targetable mutations and guides therapy

What is a tissue-agnostic therapy?

drug targeting mutations, not tissue type (e.g., Larotrectinib for NTRK fusion)

What is next-generation sequencing (NGS) used for?

Comprehensive mutation profiling (e.g., BRCA, EGFR, RAS, BRAF)

What is cancer grading based on?

histologic features: differentiation, mitotic rate, pleomorphism

What is cancer staging based on?

Tumour size, nodal involvement, metastasis (TNM system)

Which is more important for prognosis: grade or stage?

stage

In breast cancer grading, what are the 3 components scored?

tubule formation, nuclear pleomorphism, mitotic count

What is Vogelstein's model of colorectal carcinogenesis?

a stepwise accumulation of mutations in specific genes (e.g., APC → KRAS → p53) that drive progression from normal epithelium to carcinoma

Which genes are commonly mutated in Vogelstein's cascade?

APC, KRAS, p53, DCC

What is the EGFR-Ras-Raf pathway's role in cancer?

it promotes cell proliferation; mutations lead to uncontrolled growth

What does the CDK-cyclin pathway regulate?

the cell cycle; dysregulation allows unchecked progression through cell cycle phases

What is the gene translocation in chronic myeloid leukemia (CML)?

t(9;22) - BCR-ABL fusion (Philadelphia chromosome)

What gene translocation is common in Burkitt lymphoma?

t(8;14) - MYC under the control of the IgH promoter

What translocation is associated with follicular lymphoma?

t(14;18) - BCL2 under control of the IgH promoter

What is a tumour suppressor gene?

a gene that encodes proteins which inhibit cell proliferation, promote apoptosis, or repair DNA, thereby preventing carcinogenesis

How do tumour suppressor genes differ from oncogenes?

tumour suppressors act as brakes on cell division; oncogenes act as accelerators promoting proliferation

What happens if a tumour suppressor gene is lost or inactivated?

it leads to loss of growth inhibition and contributes to uncontrolled cell proliferation (a hallmark of cancer)

What is the "two-hit hypothesis" for tumour suppressor gene inactivation?

both alleles of a tumour suppressor gene must be inactivated (via mutation or deletion) for loss of function

What is the role of Rb in the cell cycle?

Rb binds to E2F and inhibits transcription of S-phase genes; phosphorylation by CDKs inactivates Rb, allowing cell cycle progression

What tumour suppressor gene encodes the p16 protein?

CDKN2A gene

What does p16 do?

p16 inhibits Cyclin D-CDK4, preventing Rb phosphorylation and halting G1/S progression

What are common alterations that disrupt the G1/S checkpoint in cancer?

loss of Rb, amplification of Cyclin D/CDK4, and deletion of CDKN2A (p16)

How does p53 promote apoptosis?

it induces transcription of pro-apoptotic genes like BAX and PUMA when DNA damage is irreparable

What is the role of BCL-2 in apoptosis regulation?

BCL-2 is anti-apoptotic; overexpression inhibits cytochrome c release from mitochondria, blocking apoptosis

What mutation is common in follicular lymphoma affecting apoptosis?

translocation of BCL-2 to the IgH region, leading to its overexpression

What are the functions of BRCA1 and BRCA2?

they mediate DNA double-strand break repair via homologous recombination

What happens when BRCA1/2 are mutated?

DNA repair is impaired, increasing the risk of breast, ovarian, and prostate cancers

What is NF1 and its function?

NF1 encodes neurofibromin, a GAP that inactivates Ras; loss leads to persistent Ras activation and tumour growth

What is APC's role in tumour suppression?

APC regulates β-catenin degradation; loss of APC leads to unchecked β-catenin activity and cell proliferation.

What is PTEN's role in tumour suppression?

PTEN dephosphorylates PIP3, downregulating PI3K/AKT signalling, thus inhibiting survival and growth pathways.

What is the link between p53, p16, Rb, and senescence?

these tumour suppressors induce senescence (permanent G1 arrest) to prevent malignant transformation

What is telomerase and how is it involved in cancer?

telomerase maintains telomere length; reactivation in cancer cells enables replicative immortality

What are the main mechanisms of cancer gene activation?

point mutations, chromosomal translocations, gene amplification, epigenetic changes, and altered miRNA expression

Give an example of oncogene activation by point mutation.

B-Raf V600E in melanoma or JAK2 V617F in MPNs

Give an example of chromosomal translocation in cancer.

BCR-ABL fusion in CML from t(9;22) Philadelphia chromosome

What is oncogene addiction?

cancer cells become dependent on a single oncogene (e.g., BCR-ABL), making it a powerful therapeutic target

How do epigenetic changes contribute to cancer?

hypermethylation silences tumour suppressor genes; global hypomethylation activates oncogenes

How does miRNA dysregulation affect cancer?

miRNA loss can increase oncogene expression (e.g., BCL-2), while overexpression may silence tumour suppressors