11.1 Recorded Lecture - Tumor Classification and Nomenclature

Tumor Classification and Nomenclature

• Benign tumors are encapsulated by connective tissue, contain well-organized cells/stroma, and retain normal tissue structure.
• Benign tumors do not invade their capsule or spread to lymph nodes/distant sites; necrotic cells are rare.
• Malignant tumors grow rapidly, exhibit loss of differentiation, and lack normal tissue organization.
• Pleomorphism in malignant tumors means cells vary in size and shape; they often have large, dark nuclei and many mitotic cells.
• Malignant tumors lack a capsule, invading blood vessels, lymphatics, and surrounding structures.
• Metastasis, the ability to spread far beyond the origin tissue, is a deadly characteristic of malignant tumors.
• Carcinoma in situ (CIS) is a pre-invasive epithelial tumor with atypical cells and increased proliferation.
• CIS lesions do not penetrate the basement membrane or invade stroma, thus not malignant.
• CIS lesions can remain stable, progress to invasive cancer, or regress and disappear.

Genetic Changes in Cancer

• Cancer is a disease of cumulative genetic changes that occur during aging.
• Point mutations (small DNA changes) and chromosome translocations (large chromosomal changes) are included.
• Gene amplification results from repeated duplications of a chromosome region.
• Driver mutations in DNA cause cells to become cancerous.
• Passenger mutations do not contribute to malignancy and cancer cells have a selective advantage.
• Clonal proliferation is when cancer cells reproduce and accumulate faster than neighboring cells.
• Malignant transformation is when a normal cell becomes cancerous through accumulated genetic changes.
• Tumor development is like Darwinian evolution, where cells gain an advantage and outcompete others.
• Heterogeneity arises from ongoing proliferation and mutation.
• Cancer is a complex genetic disease, and tumors have a heterogeneous microenvironment of cancerous and benign cells.

Hallmarks of Cancer: Uncontrolled Cellular Proliferation

• Proto-oncogenes regulate proliferation; when mutated into oncogenes, they drive unregulated cell growth.
• Autocrine stimulation occurs when cancers secrete their own growth factors, stimulating cell growth.
• Breast cancer can involve increased production of human epidermal growth factor receptor 2 (HER2), making cells oversensitive to growth factors.
• Point mutations, translocations, and gene amplification can activate oncogenes.
• Chromosome fusion (e.g., chromosomes 8 and 14 in Burkitt lymphoma) can cause inappropriate proliferation factor production.
• Chromosome fusion (e.g., chromosomes 9 and 22) can produce novel proteins that promote growth of myeloid cells, resulting in unregulated protein tyrosine kinase.
• Gene amplification increases oncogene expression.

Tumor Suppressor Genes and Genomic Instability

• Tumor suppressor genes regulate the cell cycle, inhibiting growth signals and preventing mutations.
• Inactivation of tumor suppressor genes is related to uncontrolled proliferation.
• Two mutations are needed to inactivate tumor suppressor since individuals have a copy from each parent.
• Retinoblastoma gene mutations cause childhood retinoblastoma and lung, breast, and bone cancers.
• A single germline mutation in a tumor suppressor gene leads to inherited genetic predisposition to cancer.
• Genomic instability is an increased tendency for alterations in the genome.
• Mutations in caretaker genes increase genomic instability and cancer risk.
• Hereditary non-polyposis colorectal cancer involves defects in DNA base pair mismatch repair.
• This defect causes increased rates of DNA insertions/deletions, leading to colon and other cancers.
• Genomic instability can result from increased epigenetic silencing.
• BRCA1 and BRCA2 are tumor suppressors and caretaker genes that repair double-stranded DNA breaks.
• BRCA1/2 mutations increase the risk for breast, ovarian, and prostate cancers.
• 12% of women develop breast cancer, while 60% with BRCA1 mutations develop it by age 70.

Immortality, Angiogenesis, and Aerobic Glycolysis

• Cancer cells are immortal and continue to divide, unlike normal cells that have limited divisions.
• Telomeres, protective caps on chromosomes placed and maintained by telomerase.
• Telomeres shorten with each division in normal cells, leading to cell death when critically short.
• Cancer cells activate telomerase, maintaining telomeres and allowing continuous division in 90% of cancers.
• Blood supply is essential for tumor growth and spread; tumors are limited to 1mm diameter without.
• Angiogenic factors and inhibitors regulate new vessel development.
• Hypoxia Inducing Factor 1 alpha (HIF-1α) regulates angiogenesis in normal tissue.
• Tumor suppressor gene inactivation or oncogene expression increases HIF-1α, leading to increased angiogenic factors and vascularization.
• Angiogenesis inhibitors bind to cellular surface receptors on inflammatory cells, negatively regulating angiogenesis.
• p53 protein controls expression of these inhibitors, but it is suppressed in cancer cells.
• Malignant tumors secrete angiogenic factors and tissue remodeling matrix, inducing new blood vessel formation.

Aerobic Glycolysis, Evading Apoptosis and Chronic Inflammation

• Normal cells generate 36 ATP molecules via mitochondrial oxidative phosphorylation in the presence of oxygen.
• Normal cells generate 2 ATP molecules and lactic acid/pyruvate via glycolysis in the absence of oxygen.
• Cancer cells primarily use glycolysis, even with sufficient oxygen.
• Products of glycolysis are used for lipids, nucleotides, amino acids, and other building blocks.
• Oncogenes and mutated tumor suppressor molecules activate promoters of aerobic glycolysis.
• Oncogenes increase glucose transport into the cytoplasm, supporting rapid cancer growth.
• Apoptosis is programmed cell self-destruction used during tissue remodeling.
• The intrinsic apoptosis pathway monitors cellular stress (DNA damage, etc.).
• The extrinsic pathway goes through a plasma membrane death receptor linked to intracellular activators.
• Both pathways activate caspase-3, which cuts DNA and leads to cell death.
• Apoptotic pathways are dysregulated in most cancers, increasing resistance to cell death.
• Chronic inflammation is a factor in cancer development, onset, and progression.
• Chronic inflammation results from asbestos exposure, pancreatitis, or infection.
• Individuals with ulcerative colitis for 10+ years have a 30-fold increased risk of colon cancer.
• Tumors manipulate the inflammatory response to induce tissue damage, proliferation, vascularization, and immune suppression.
• Tumor-associated macrophages (TAMs) have diminished cytotoxic responses and block T cytotoxic/natural killer cell functions.
• TAMs produce cytokines that advantage tumor growth/spread, increasing tumor growth, blood vessel invasion, oxygen, and tissue invasion.

Immune Surveillance, Immunotherapy, and Metastasis

• Cancer cells express surface antigens not usually found on normal cells.
• Natural killer cells should recognize and destroy these foreign cells.
• The two resulting theories are the immune surveillance hypothesis and immunotherapy.
• The immune surveillance hypothesis is that malignancies are suppressed by an immune response against tumor-associated antigens.
• Immunotherapy predicts the immune system can target tumor-associated antigens and destroy tumors.
• Immunotherapy can be activated by immunization, enhancing a particular cancer, or injecting antibodies/lymphocytes against tumor antigens.
• Most cervical cancer is caused by HPV infection, which the immune system handles rapidly.
• Early detection of atypical cervical cells alerts to the possibility of cervical carcinoma in situ in Pap tests.
• Vaccines for oncogenic HPV types prevent many cervical cancer cases.
• Immunosuppressant drugs for transplant increase non-Hodgkin lymphoma risk tenfold and Kaposi's sarcoma risk thousandfold, but only increase colon/lung cancer risk slightly.
• Contributing factors are immunosuppressive factors and adaptive mechanisms of tumor cells.

Metastasis, Epithelial-Mesenchymal Transition (EMT)

• Metastasis is a defining characteristic of cancer and the major cause of death from cancer.
• Surgery, chemotherapy, and radiation are ineffective against metastatic cancer.
• Localized breast cancer has a five-year survival rate of 90%, while metastatic cancer has less than 30%.
• Epithelial-mesenchymal transition (EMT) - cancer cells obtain abilities that facilitate metastasis.
• Primary neoplastic cells retain epithelial-like characteristics that prevent dissociation from the extracellular matrix and preclude successful metastasis to distal sites.
• A greater degree of cellular differentiation is necessary to produce a cell that can separate from the primary tumor and flourish in a potentially hostile secondary site.
• EMT typically occurs in normal embryonic development, wound healing, and tissue repair.
• Cells undergoing EMT have suppressed adhesion molecule expression with a loss of polarity, increased modulatory capacity, and elevated resistance to apoptosis, and have demonstrated the potential to re-differentiate into other types of cells.
• EMT is typically driven by cytokines and chemokines, especially interleukin-8, produced within the tumor microenvironment.
• TGF-beta, secreted by the tumor stroma, is a major mediator of EMT.
• Mesenchymal cells survive in the circulation by associating with platelets/clotting factors, shielding them from cytotoxic immune cells.
• At a metastatic site, cancer cells adhere to the local vascular endothelium and undergo mesenchymal-epithelial transition to begin life at the new site.

Paraneoplastic Syndromes, Cancer Treatments

• Paraneoplastic syndromes are caused by biologic substances released by the tumor or the immune response triggered by a tumor.
• These syndromes may be the earliest symptom of an unknown cancer, and can be serious or life-threatening.
• Cachexia is an energy balance disorder with decreased energy intake and increased expenditure.
• It is hypothesized that activation of a mitochondrial protein interacts with the muscle sarcoplasmic reticulum controlling organelle calcium.
• Calcium deregulation and muscle wasting results.
• Muscle wasting in cancer is due to increased apoptosis and impaired regeneration capacity.
• Cachexia includes loss of white adipose tissue caused by increased lipolysis and decreased new lipogenesis.
• A person often feels full after only a few mouthfuls of food.
• Cytokines alter brain pathways that regulate food intake.
• Surgery is often definitive for cancers that do not spread beyond surgical excision limits.
• Surgery is indicated for relief of symptoms caused by tumor mass obstruction.
• Adequate surgical margins during resection prevent local recurrences.
• Adequate tissue specimens during biopsy provide confident diagnosis.
• Surgeons get staging information by sampling/removing local and regional lymph nodes.
• Radiation therapy kills cancer cells while minimizing damage to normal structures by imparting enough energy to cause molecular damage, especially to DNA.
• Rapidly renewing cells are more radiosensitive.
• Radiation treats localized disease in areas that are hard to treat surgically (brain, pelvis).
• Brachytherapy capsules are temporarily placed into body cavities to deliver radiation for cervical, prostate, and head/neck cancers.
• Chemotherapeutic agents attack pathways that exist in rapidly dividing normal and cancer cells.
• Cancer cells utilize these pathways more and are severely affected.
• Leukemia and other cancer cells are exquisitely sensitive to folic acid and asparagine deprivation.
• Some cancer cells are highly sensitive to DNA damaging agents.
• Single chemotherapeutic agents shrink cancers but are rarely given alone.
• Chemotherapy is usually given in combination designed to attack cancer from many different weaknesses at the same time to limit dose and toxicity.
• A major complication of chemotherapy is death of rapidly dividing cells that are not cancer, such as those in the bone marrow.
• Tumor cell vaccines have not been shown to be effective as of yet.
• Vaccines against B-cell lymphoma and melanomas have shown promising results.
• A family of monoclonal antibodies are currently approved for use against cancer that is designed to directly bind to and damage cancer cells.
• Immune checkpoint inhibitors are molecules that may suppress or allow T cell mediated cytotoxicity, thus protecting normal cells.
• Antibodies are directed against molecules involved in repressing T-cell immune responses.
• Drugs are available for advanced melanoma, urethral carcinoma, non-small cell lung cancer, and renal cell carcinoma.
• Targeted cancer therapy addresses unique growth characteristics of a specific tumor class and directly interferes with that process.
• More than 25 drugs have been developed as cancer targeting agents that inactivate oncogenes, block angiogenesis and affect cancer cell metabolism.