Cancer Metastasis and Staging Quiz

Lecture 12: Neoplasm and Cancer Therapy

• Learning Outcomes: Students should be able to identify, describe, and differentiate concepts of cell differentiation and growth, cancer and cell cycle checkpoints, oncogenes and tumor suppressor genes, benign and malignant tumor differences, classification of neoplasia, etiology of malignant neoplasia, clinical manifestation, and diagnosis and treatment.

Cancer Terminology

• Dysplasia: Abnormal development of tissues.
• Mutant Cells: Disruption of RNA and DNA within normal cells resulting in cells differing in form and function from normal cells.
• Neoplasm/Tumor: Abnormal new growth of cells (not necessarily cancer).
• Benign Tumors: Cells are encapsulated, well-differentiated, with normal tissue structure, do not invade other tissues. May or may not transform to malignancy.
• Malignant Tumors: Arise from abnormal and uncontrolled cell proliferation, invading and destroying surrounding tissues.
• Primary Tumor: The original site where the tumor arises.
• Invasion: The process where cancer cells invade surrounding tissues.
• Metastasis: The process where cancer cells spread to distant sites via the bloodstream or lymph or across body cavities to form secondary tumors.
• Anaplasia: A typical malignant tumor where cells are poorly differentiated.
• Angiogenesis: The formation of new blood vessels to supply nutrients for tumor growth.
• Tumorigenesis: The process of tumor formation.
• Carcinogenesis: The process where normal cells transform into cancer cells.

Proliferation and Differentiation

• Proliferation: The process of increasing cell numbers by mitotic cell division (mitosis).
• Differentiation: The process whereby proliferating cells become more specialized.
• Apoptosis: A form of programmed cell death that eliminates injured or unwanted cells.

The Normal Cell Cycle

• The duration of the cell cycle varies between cell types (10-30 hours in mammalian cells).
• The phases must follow in a specific order, with errors in coordination leading to chromosomal alterations.
• Coordination is determined by cyclins and cyclin-dependent kinases (CDKs).

Cellular Adaptation

• Atrophy: Decrease in cell size.
• Hypertrophy: Increase in cell size.
• Hyperplasia: Increase in cell number.
• Metaplasia: Change in cell type.
• Dysplasia: Abnormal cell size, shape, appearance, and differentiation.

What is Cancer?

• Cancer is characterized by uncontrolled differentiation and growth, spread of abnormal cells.
• New cells are only formed for growth or to replace dead ones.
• Cancerous cells do not self-destruct; they divide rapidly.
• No apoptosis function.
• Mutated genes have altered DNA sequences from normal genes.
• Mutations may result in cancer development.
• Factors that bring about DNA mutation are called mutagens.
• Cancer-causing agents are called carcinogens.
• Mutagens are often carcinogenic.

How do Normal Cells Become Cancerous?

• Several mutations are required for normal cells to become cancerous.
• Cells proliferate too much and may look abnormal.
• Structural changes occur.
• Selection occurs within the tumor for the "most cancerous" cells.

Oncogenes, Tumor Suppressor Genes, and Cancer

• Proto-oncogenes: Normal genes involved in regulating cell proliferation.
• Mutated proto-oncogenes transform into oncogenes that promote uncontrolled cell proliferation and cancer development. Example: RAS oncogene.
• Tumor Suppressor Genes: Encode proteins that inhibit tumor formation when DNA is damaged, stop cell division, and induce apoptosis.
• Mutated tumor suppressor genes lose their ability to prevent DNA damage and uncontrolled cell proliferation. Example: TP53 gene.

Possible Types of Mutations Leading to Oncogene Activation

• Deletion
• Duplication
• Inversion
• Reciprocal translocation

Oncogene Activation by Chromosomal Translocation

• Chronic Myelogenous Leukemia (CML): Reciprocal translocation between chromosomes 9 and 22 creates the Philadelphia chromosome (Ph1), leading to a hybrid oncogenic protein (bcr-abl).

The Mutation of Tumor Suppressor Genes

• Tumor suppressor genes produce normal proteins that control cell growth.
• When mutated, these genes cannot produce normal proteins, lose control of cell growth, cell division becomes uncontrolled, resulting in a limited number of cells and size.

Examples of Tumor Suppressor Genes

• Retinoblastoma gene (Rb gene): Loss or mutation accelerates the cell cycle, increasing proliferation in retinoblastoma.
• Adenomatous polyposis coli (APC) gene: Mutations lead to familial adenomatous polyps (FAP).
• Tumor protein TP53 (p53) gene: Normally activated in DNA-damaged cells promoting apoptosis; inactivation leads to cell survival.

Genetic Events Leading to Loss of Tumor Suppressor Gene Function

• Loss of heterozygosity: The normal tumor suppressor gene copy is either inactivated or mutated.
• Two-hit hypothesis: Cancer develops when sufficient mutations have occurred within a lifetime of mutations that lead to cancer development.

Hallmarks of Cancer

• Cell acquires 8 essential alterations in cell physiology.
• This occurs due to the multistep development of cancer.
• Two additional characteristics enable cancer progression.

Enabling Replicative Immortality

• Telomeres protect chromosome ends from deterioration or fusion.
• Telomeres shorten with each division until cell division stops.
• Normal cells cannot divide indefinitely.
• Telomerase is an enzyme for telomere elongation, active in stem cells and most cancer cells.
• In cancer cells, the enzyme rebuilds telomeres, enabling immortality, and the ability to divide indefinitely.

Risk Factors of Developing Cancer

• High consumption of certain food substances (e.g., omega-6 fatty acids, grilled/preserved foods).
• High calcium intake (> 2000 mg).
• High-glycemic-index carbohydrates.
• Ionizing radiation (e.g., X-rays, UV light).
• Chemicals (e.g., tar from cigarettes).
• Obesity.
• Alcohol consumption.
• Lack of exercise.
• Bacterial and viral infections (e.g., Helicobacter pylori, HPV).
• Hereditary predisposition (e.g., BRCA1 & BRCA2 for breast cancer).

Benign or Malignant Tumor?

• Benign Tumors: Do not spread from their origin, but can crowd out surrounding cells (e.g., brain tumors, warts).
• Malignant Tumors: Can spread to form secondary tumors (metastasis). Both types of tumors need nutrients for rapid growth.

Benign vs Malignant Tumor

• Benign: well-differentiated cells, progressive and slow growth, usually encapsulated.
• Malignant: undifferentiated cells, rapid growth, not encapsulated, invades surrounding tissues, and gains access to blood/lymph channels to spread.

Morphology of Cancer Cells

• Anaplasia: Loss of cell differentiation.
• Pleomorphism: Variations in cell and nuclei size and shapes.
• Nucleoli: Larger than normal in most nuclei.
• Chromatin/Chromosomes: Coarse and clumped.

Metastasis

• Cancer cells can invade nearby tissues or metastasize (spread) to other organs.
• Cancer cells may spread via three routes: venous system, lymphatic system, seeding.

Mechanisms of Tumor Metastasis

• Cancer cells disrupt and invade extracellular matrix.
• Release of proteolytic enzymes degrades extracellular matrix, allowing cancer cells to migrate.
• Cancer cells penetrate basement membrane.
• Cancer cells spread through blood vessels or lymphatics to other parts of the body.

Diagnosis of Cancer

• Investigation of symptoms depends on cancer location.
• Imaging techniques (MRI, X-ray, CT scan) are used for diagnosis.
• Tumor markers are substances produced by cancer cells found in blood, spinal fluid, or urine; some are sensitive and specific for certain cancers (e.g., cervical cancer, and colorectal cancer).
• Tumor tissue biopsy is used for identifying cancer stages (e.g., Papanicolaou or PAP smear for cervical cancer, colonoscopy for colorectal cancer).

Manifestations & Prognosis of Cancer

• Cachexia: Severe malnutrition with anorexia, early satiety, and weight loss, present in 80% of cancer patients at death.
• Anemia: Decrease in hemoglobin concentration in blood due to chronic bleeding, resulting in iron deficiency, malnutrition. Medical treatments or malignancy in blood-forming organs.
• Prognosis is linked to cancer type, and tumor size, lymph node involvement, and metastasis.

Staging of Cancer

• Staging: Determined by tumor size and extent of local invasion, spread to regional structures, and distant sites.
• TNM system: Used to categorize tumors based on primary tumor (T), lymph node (N), and metastasis (M) factors.

Colorectal Cancer

• Common cancer in men and women.
• 90% of colorectal cancers are preventable.
• Risk factors: age over 50, obesity, family history, diets high in fat, low in fiber, smoking, high alcohol consumption, and lack of exercise.

Four Main Types of Leukemia

• Acute Lymphoid Leukemia (ALL): Most common in children.
• Acute Myeloid Leukemia (AML): Most common in adults, rapid dividing, myeloid cells.
• Chronic Lymphoid Leukemia (CLL): Slow-growing, mature cells.
• Chronic Myeloid Leukemia (CML): Affects myeloid cells, slow progression.

Nasopharyngeal Carcinoma (NPC)

• Gender: Male more often than female.
• Risk factors: Diet (salted cured fish), smoking, EBV infection, Family history and environment.

Breast Cancer

• Estrogen receptor-positive breast cancer cells proliferate due to estrogen and are inhibited by tamoxifen.
• Estrogen receptor-negative breast cancer cells proliferation is not controlled by estrogen, and not inhibited by tamoxifen.

Investigations of Breast Cancer

• Mammogram: Breast imaging to look for tumors.
• Biopsy: Fine needle aspirate (FNA) for testing.
• Inherited mutations (BRCA, HER2)
• Estrogen receptor (ER) positive: Hormonal therapy.
• Breast lumps detected by mammograms.

Hormonal Therapy for Breast Cancer

• Selective estrogen receptor modulators (SERMs): Examples include tamoxifen.
• Aromatase inhibitors (AIs): Examples include anastrozole, exemestane, letrozole.
• Estrogen receptor downregulators (ERDs): Examples include fulvestrant.

Treatment of Breast Cancer

• Surgery: Lumpectomy, quadrantectomy, mastectomy, breast-conservative surgery.
• Radiation therapy: Treats tumors.
• HER2 +ve Breast Cancer: Trastuzumab, Laptinib

Targeted Cancer Therapy (TKI)

• Tyrosine kinases: Protein activation by phosphorylation.
• TKI: Inhibitory signaling pathways, promoting tumor survival and growth.
• Examples: Imatinib, pazopanib, sunitinib. These medicines target signaling proteins in cancer cells and prevent signal transduction pathways to stop proliferation and growth.

Other Cancer Treatments

• Conventional treatments: Surgery, radiation, chemotherapy, or a combination.
• New possible treatments: Immunotherapy, cancer-fighting vaccines, stem cell research, and gene therapy.

Notable Side Effects of Chemotherapy

• Severe Emesis: Acute and delayed nausea/vomiting.
• Photosensitivity: Increased sensitivity to light.
• Pulmonary toxicity: Lung damage.
• Neurotoxicity: Nerve damage.
• Hepatotoxicity: Liver damage.
• Ulcers: Sores in the lining of the digestive tract.
• Renal toxicity: Kidney damage.
• Hemorrhagic cystitis: Blood in the urine.

Test your knowledge on cancer metastasis pathways and the staging system used to evaluate cancer progression. This quiz covers important concepts such as the role of lymph nodes, the TNM system, and classification of tumor sizes. Improve your understanding of how cancer spreads within the body.