Tumor Biology: Benign vs. Malignant

• Benign tumors are encapsulated, contain well-differentiated cells, and have organized stroma.
• These tumors retain recognizable tissue structure and do not invade or spread.
• Mitotic cells are rare in benign tumors.
• Malignant tumors grow rapidly, lose differentiation, and disorganize normal tissue.
• They exhibit decreased cellular differentiation, variability in size and shape, darkly stained nuclei, and mitotic cells.
• Malignant tumors lack a capsule, invade vessels and surrounding structures, and can metastasize.
• Metastasis is the most important characteristic of malignant tumors.
• Carcinoma in situ is a preinvasive epithelial tumor that hasn't penetrated the basement membrane.
• It can remain stable, progress to invasive cancer, or regress.
• Uncontrolled cellular proliferation is a primary hallmark of cancer cells.
• Cancer cells display immortality.
• Point mutations are small-scale DNA changes altering nucleotide pairs.
• Chromosome translocation involves large-scale changes where chromosome pieces move.
• Gene amplification results in numerous copies of a chromosome region.
• Driver mutations propel cancer progression.
• Passenger mutations are random events that may not contribute to malignancy.
• Clonal proliferation/expansion gives cancer cells a selective advantage for rapid accumulation.
• Malignant transformation is how a normal cell becomes cancerous through progressive genetic changes, resembling Darwinian evolution.

Stroma and Oncogenes

• Stroma is the tumor microenvironment that surrounds and infiltrates the tumor.
• Stromal cells produce excessive growth factors that drive cancer cell proliferation.
• Proto-oncogenes encode components regulating normal cellular proliferation.
• Oncogenes, mutated or overexpressed proto-oncogenes, lead to unregulated cell growth.
• Gene amplification can activate oncogenes, increasing expression or creating drug resistance.
• Autocrine stimulation enables some cancers to secrete growth factors that promote their own growth.
• HER2 is upregulated in breast cancers; inhibitors can effectively treat certain breast and lung cancers.
• Translocations can activate oncogenes, causing excess production; the 8,14 translocation in Burkitt lymphomas is an example.
• The 9, 22 translocation is associated with CML.

Tumor Suppressor Genes and Genomic Instability

• Tumor suppressor genes regulate the cell cycle, inhibit proliferation, stop cell division when cells are damaged, and prevent mutations.
• Inactivation of tumor suppressor genes causes uncontrolled cancer cell proliferation.
• The retinoblastoma gene is a tumor suppressor gene mutated in retinoblastoma, breast, lung, and bone cancers.
• P53 is a tumor-suppressing gene that monitors and activates caretaker genes.
• Genomic instability is an increased tendency for genomic alterations throughout a cell's life.
• Mutations in caretaker genes elevate genomic instability, increasing cancer risk.
• Hereditary nonpolyposis colorectal cancer results from a DNA mismatch repair defect.
• Genomic instability can result from increased epigenetic silencing or modulation.
• BRCA1 & BRCA2 mutations increase the risk for breast cancer in men and women; often resulting in cancer by age 70

Angiogenesis, Metabolism, and Apoptosis

• Angiogenesis, access to blood supply, is required for cancer growth and spread.
• Without angiogenesis, tumors are limited to a millimeter in diameter.
• Inactivation of tumor suppressor genes or increased expression of oncogenes leads to increased vascularization.
• The Warburg effect is the use of glycolysis by cancer cells even with adequate oxygen.
• The Warburg effect allows more efficient production of lipids, nucleosides, and amino acids.
• This effect can be induced by the upregulation of GLUT1, regulated by oncogenes and mutant tumor suppressors.
• Cancer cells can resist apoptotic cell death, which is normally a protective mechanism.
• Dysregulation of apoptosis pathways, often due to P53 loss, occurs in most cancers.
• Caspases, like Caspase 3, are intracellular enzymes activated by apoptosis pathways, cleaving DNA and causing cell death.

Inflammation, Immune Response, and Metastasis

• Chronic inflammation from various sources is a factor in cancer development.
• Ulcerative colitis increases colon cancer risk.
• Successful tumors can manipulate the acute inflammatory response.
• Tumor-associated macrophages (TAMs) promote tumor survival and block T-cytotoxic and NK cell functions.
• TAMs produce cytokines that benefit tumor growth, invasion, and oxygen supply.
• Immune Surveillance predicts that the immune response suppresses most malignancies.
• Cancer cells develop mechanisms to evade immune surveillance.
• Defective immune responses increase the risk for lymphoid cancers.
• Immunotherapy can be active, using immunization, or passive, injecting antibodies or lymphocytes.
• Metastasis is the defining characteristic of cancer and the major cause of cancer death.
• Cancer that has not metastasized can often be cured.
• Paraneoplastic syndromes are triggered by cancer, but not by local tumor effects, and can be early symptoms.
• Cachexia is a multi-organ syndrome with decreased energy intake and increased expenditure.
• Muscle wasting and loss of white adipose tissue result from increased lipolysis and decreased lipogenesis.
• Early satiety and a feeling of fullness are common in cancer patients.
• Tumor Markers are substances produced by benign and malignant cells, found in blood, spinal fluid, or urine.