Neoplasia and Cancer Biology Notes

Neoplasia & Cancer Biology

Cell Adaptation Review

• Atrophy: Cells become smaller.
• Hypertrophy: Increase in cell size.
• Hyperplasia: Increase in cell number.
• Metaplasia: Change in cell type.
• Dysplasia: Abnormal cell growth; always indicates abnormality.
• Neoplasia: New, uncontrolled growth; diagnosed as cancer.
• Trophy: Growth.
• Plasia: Growth.
• Hyper: Large cells, large number of cells.
• Meta: Change in growth.
• Dys: Always means abnormal.

Cancer Definition

• Derived from the Greek word "karkinoma," meaning crab.
• Another term for a malignant tumor.
• Not simply a tumor; it's an abnormal growth resulting from uncontrolled proliferation.
• Serves no physiological function.
• Referred to as a neoplasm (new growth).

Characteristics of Cancer/Neoplasm

• Disorder of altered cell differentiation and growth.
• Results in neoplasia (new growth).
• Does not follow normal cell growth laws.
• Uncoordinated and relatively autonomous growth.
• Lacks normal regulatory controls over cell growth and division.
• Continues to grow even after the stimulus ceases or organism's needs are met.

Benign vs. Malignant Tumors

Classification and Nomenclature

Benign Tumors

• Named after the tissue of origin with the suffix "-oma".
  • Lipoma: Fat tissue tumor
  • Leiomyoma: Smooth muscle tumor

Malignant Tumors

• Named according to tissue of origin.
  • Malignant epithelial tumors: Carcinomas
  • Malignant connective tissue tumors: Sarcomas
  • Cancers of lymphatic tissue: Lymphomas
  • Cancers of blood-forming cells: Leukemias
  • Adenocarcinoma: Ducts or glands

Carcinoma in situ (CIS)

• Preinvasive epithelial malignant tumors of glandular or squamous origin.
• Has not penetrated the basement membrane or invaded surrounding stroma.
• Not considered malignant.
• Prognoses:
  • Can remain stable for a long time.
  • Can progress to invasive and metastatic cancers.
  • Can regress and disappear.

Characteristics of Benign Neoplasms

• Slow, progressive growth rate that may stop or regress.
• Expansive growth pattern.
• Inability to metastasize.
• Composed of well-differentiated cells resembling the tissue of origin.

Characteristics of Malignant Neoplasms

• Tend to grow rapidly and spread widely.
• Can cause death regardless of original location.
• Compress blood vessels and outgrow their blood supply, leading to ischemia and tissue necrosis.
• Deprive normal tissues of essential nutrients.
• Release enzymes and toxins that destroy tumor and normal tissues.

Biology of Cancer Cells

• Clonal proliferation or expansion occurs due to a mutation.
• Mutation gives the cell a selective advantage over neighbors.
• Increased growth rate or decreased apoptosis.
• Multiple mutations are needed for cancer to develop.

Mutation Details

• Mutation: Alteration in DNA sequence affecting gene expression or function.
• Point mutations: Small-scale changes.
• Driver mutations: Drive cancer progression.
• Passenger mutations: Random events.
• Gene amplification: Repeated duplication of chromosome regions, resulting in many copies of a gene.

Chromosome Translocation

• Large changes in chromosome structure.
• A piece of one chromosome is translocated to another chromosome.
• Clonal proliferation (clonal expansion): Cancer cell progeny accumulate faster than non-mutant neighbors.

Malignant Transformation

• Process during which a normal cell becomes a cancer cell.
• Results in a heterogeneous mixture of cancer cells.
• Stroma: Tumor microenvironment.
• Cancer heterogeneity: Due to proliferation and mutation.
• Cancer development is similar to wound healing.

Oncogenes and Tumor-Suppressor Genes

• Three key genetic mechanisms in human carcinogenesis:
  • Activation of proto-oncogenes, resulting in hyperactivity of growth-related gene products (oncogenes).
  • Mutation of genes results in loss or inactivity of gene products that would normally inhibit growth (tumor-suppressor genes).
  • Mutation of genes results in overexpression of products that prevent normal cell death or apoptosis, thus allowing continued growth of tumors.

Oncogenes

• Mutant genes that, in their non-mutant state (proto-oncogenes), direct protein synthesis and cellular growth.

Tumor-Suppressor Genes

• Encode proteins that negatively regulate proliferation.
• Also referred to as anti-oncogenes.

Proto-oncogenes

• Normal, non-mutant genes that code for cellular growth.

Genomic Instability

• Results from epigenetic silencing (modulation of gene expression).
• Mutations in caretaker genes (that protect the genome and DNA repair mechanisms) increase genomic instability and the risk of cancer.

Telomeres and Immortality

• Body cells are not immortal and can divide only a limited number of times (Hayflick limit).
• Telomeres: Protective caps on each chromosome, maintained by telomerase.
• Telomeres shorten with each cell division.
• Cancer cells can activate telomeres, leading to continued division and effectively immortality.

Angiogenesis

• Growth of new blood vessels; also called neovascularization.
• Advanced cancers secrete angiogenic factors to facilitate tumor feeding.
• Key factors: Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF).

Cancer Metabolism

• Cancer cells perform glycolysis, even in the presence of oxygen (Warburg effect).
• Allows lactate and its metabolites to be used for the more efficient production of lipids and other molecular building blocks needed for rapid cell growth.

Inflammation as a Cause for Cancer

• Chronic inflammation is an important factor in cancer development.
• Active inflammation predisposes individuals to cancer by stimulating a wound-healing response (proliferation, new blood vessel growth).
• Susceptible organs: Gastrointestinal (GI) tract, pancreas, thyroid gland, prostate, urinary bladder, pleura, skin.
• Examples:
  • Ulcerative colitis (10+ years) increases the risk of colon cancer.
  • Hepatitis B (HBV) or hepatitis C (HCV) increase the risk of liver cancer.
  • H. pylori increases the risk of stomach cancer.

Tumor-Associated Macrophages (TAMs)

• Key cells promote tumor survival.
• Block cytotoxic T cell and natural killer (NK) cell functions.
• Produce cytokines advantageous for tumor growth and spread.
• Secrete angiogenesis factors.

Immune System and Viral-Associated Cancers

• Tumor-associated antigens: Oncogenes, antigens from oncogenic viruses, oncofetal antigens, and altered glycoproteins and glycolipids.
• Immune surveillance hypothesis: The immune system recognizes and destroys cancer cells.
• Immunotherapy hypothesis: The immune system can be harnessed to fight cancer.

Immunotherapy

• Active: Immunization with tumor antigens to elicit or enhance an immune response.
• Passive: Injecting antibodies or lymphocytes directed against tumor-associated antigens.

Viruses Associated with Cancer

• Human papillomavirus (HPV): Cervical cancer.
• Epstein-Barr virus (EBV).
• Kaposi sarcoma herpesvirus (KSHV or HHV8).
• Human T-cell lymphotropic virus type I (HTLV-1).
• Hepatitis B (HBV): Hepatocellular carcinoma.
• Hepatitis C (HCV): Hepatocellular carcinoma.

Cancer Invasion and Metastasis

• Metastasis: Spread of cancer cells from the original tumor site to distant tissues and organs.
• Complex process requiring cells to:
  • Spread.
  • Survive.
  • Proliferate in distant locations.
  • Find a receptive destination.

Invasion (Local Spread)

• Prerequisite for metastasis; the first step in the metastatic process.
• Cancer often spreads first to regional lymph nodes via the lymphatic system, then to distant organs via the bloodstream.
• Requires cancer cells to attach to specific receptors and survive in the specific environment.

Cancer Cell Mechanisms

• Cancer cells secrete proteases that digest the extracellular matrix and basement membranes, creating pathways for movement.
• Metastatic cells must withstand physiological stresses of travel in blood and lymph.
• Metastatic cells must survive in a new environment.

Epithelial-Mesenchymal Transition (EMT)

• Loss of epithelial-like characteristics (polarity, adhesion to basement membrane).
• Increased migratory capacity.
• Increased resistance to apoptosis.
• Dedifferentiation to a stem cell-like state favors growth in foreign microenvironments and establishment of metastatic disease.

Clinical Manifestations of Cancer

• Paraneoplastic syndromes: Symptom complexes triggered by cancer but not caused by direct local effects of the tumor mass.
• Caused by biologic substances released from the tumor (e.g., hormones) or by an immune response triggered by the tumor.
• Can be life-threatening.

Cachexia

• The most severe form of malnutrition associated with cancer.
• Leads to protein-calorie malnutrition and progressive wasting.
• Manifestations: Anorexia, early satiety, weight loss, anemia, asthenia, taste alterations, altered protein, lipid, and carbohydrate metabolism.

Diagnosing and Staging

• Involves tumor size, degree of invasion, and extent of spread.
  • Stage 1: Confined to the organ of origin.
  • Stage 2: Locally invasive.
  • Stage 3: Advanced to regional structures.
  • Stage 4: Spread to distant sites.

TNM Staging System (World Health Organization)

• T: Primary tumor (size and local extent)
  • T0: Breast free of tumor
  • T1: Lesion < 2 cm in size
  • T2: Lesion 2-5 cm
  • T3: Skin and/or chest wall involved by invasion
• N: Lymph node involvement (a higher number means more nodes are involved)
  • N0: No axillary nodes involved
  • N1: Mobile nodes involved
  • N2: Fixed nodes involved
• M: Extent of distant metastases
  • M0: No metastases
  • M1: Demonstrable metastases
  • M2: Suspected metastases

Tumor Markers

• Substances produced by benign or malignant cells.
• Found on or in a tumor cell, in the blood, in the spinal fluid, or in urine.
• Examples:
  • Hormones
  • Enzymes
  • Genes
  • Antigens
  • Antibodies

Specific Tumor Markers

• Liver and germ cell tumors secrete alpha-fetoprotein (AFP).
• Prostate tumors secrete prostate-specific antigen (PSA).
• If a tumor marker has biological activity, symptoms are expressed; this is known as a paraneoplastic syndrome.

Uses of Tumor Markers

• Screening and identifying high-risk individuals.
• Diagnosing specific types of tumors.
• Following the clinical course of cancer.

Cancer Treatment

Surgery

• Definitive treatment for cancers that have not spread beyond surgical excision limits.
• Palliative surgery can relieve symptoms.
• Prophylactic surgery can prevent cancer in high-risk individuals.
  • Colectomy for APC gene mutations (high risk of colon cancer).
  • Prophylactic mastectomy or bilateral salpingo-oophorectomy (or both) for BRCA1/2 mutations (high risk of breast and ovarian cancer).
• Must achieve adequate surgical margins to ensure complete removal.
• Surgery provides critical staging information.

Radiation Therapy

• Kills cancer cells while minimizing damage to normal structures.
• Ionizing radiation causes molecular damage to DNA, leading to cell death.
• Can cause irreversible damage to normal cells; lifetime radiation dose must be considered.
• Brachytherapy: Implantation of radioactive seeds.

Chemotherapy

• Eradicates enough tumor cells to allow the body’s natural defenses to eliminate the remaining cells.
• Can be a single-agent or combination chemotherapy.
• Induction chemotherapy: Causes shrinkage or disappearance of tumors.
• Adjuvant chemotherapy: Administered after surgical excision to eliminate micrometastases.
• Neoadjuvant chemotherapy: Administered before localized treatment (surgery or radiation).