BIOMED SCIE LECTURE 26 CANCER3

• Angiogenesis


  The physiological process involving the growth of new blood vessels from pre-existing vessels
• Angiogenesis


  • A normal and vital process in growth and development, as well as in wound healing
  • A fundamental step in the transition of tumors from a dormant state to a malignant one
  • Tumors can secrete molecules to induce blood vessel formation, the most important being vascular endothelial growth factor (VEGF)
• Metastasis


  Process in which cells from the primary tumor site escape, travel to a new location via the circulatory or lymphatic system, and establish a secondary tumor
• Metastasis


  1. Individual cells break loose from the primary mass

  2. Cells penetrate the basement membrane and degrade the extracellular matrix (ECM) of tissue, facilitated by the secretion of extracellular proteases, such as Matrix Metalloproteinases (MMPs)

  3. MMPs degrade the protein and proteoglycan components of the basal lamina, e.g., collagens allowing the cancer cell to migrate

  4. Most of the escaped cancer cells are targeted by the immune system (because cells may present novel surface antigens)

  5. To establish a secondary tumor, cells extravasate from the bloodstream into tissues – also requires protease activity
• Some cancers show organ preference. The most common sites of distant metastases are lungs, liver, bone
• Local concentrations of growth factors and hormones play a role in where cells establish a new colony
• Staging and grading of cancers

  The stage of cancer (usually numbers I to IV with IV having more progression) documents the size of the tumor and extent the cancer has spread
• Cancer stages


  • Stage 0 carcinoma in situ
  • Stage I cancers are localized to one part of the body
  • Stage II cancers are locally advanced
  • Stage III cancers are also locally advanced. Lymph nodes affected
  • Stage IV cancers have often metastasized or spread to other organs or throughout the body
• Tumor Markers


  Cancer cells often show a phenotype typical of less differentiated embryonic cells – e.g., some can make AFP (alpha fetoprotein) not normally made in adults – can be a useful marker for diagnosis
• Cancer Prevention


  • Anti-viral vaccines like the HPV vaccine can prevent infection and the risk of cervical cancer
  • Prevent exposure to high toxicity carcinogens e.g., asbestos (Mesothelioma), dioxins i.e., TCDD, toxic metals e.g., chromium 6
  • Promoting awareness and recommending limited exposure e.g., UV radiation, smoking, etc.
• Cancer treatment


  • Surgery
  • Radiotherapy with ionizing radiation
  • Chemotherapy using chemicals to kill cancer cells - traditional small molecule drugs and newer biologics (immunotherapy / hormone blockers)
• The challenge is to kill cancer cells without harming normal human cells
• Traditional treatments target rapidly dividing cells. But...most treatments have side effects, especially on normal cells that also divide relatively rapidly e.g., hair follicles, immune system cells
• Anti-cancer therapies


  • Radiotherapy – Ionizing radiation causes extensive DNA damage and induces apoptosis
  • Chemotherapy involves Alkylating agents for DNA damage e.g., cisplatin, Antimetabolites that target DNA building block synthesis e.g., methotrexate, 5-FU, and Topoisomerase inhibitors for DNA replication and repair
  • Mitotic inhibitors e.g., microtubulin-binding agents cause cell cycle arrest
  • Methotrexate inhibits the enzyme dihydrofolate reductase involved in nucleotide synthesis (purine and pyrimidine biosynthetic pathways) thus blocking DNA synthesis in rapidly dividing cancer cells, acting as a substrate for enzymes and being a competitive inhibitor
• Receptor-targeted therapy for Breast Cancers (Hormone Therapy)


  Some breast cancers have elevated levels of the estrogen receptor where estrogen binding contributes to cell growth. Cells are ER+ (estrogen receptor positive). Tamoxifen binds the receptor and blocks estrogen - currently used for the treatment of both early and advanced ER+ breast cancer. Another sub-group of breast cancers overexpress the Human Epidermal Growth Factor Receptor 2 (HER2+). Recent treatment with an antibody targeting this receptor (Herceptin = trastuzumab – monoclonal antibody)
• Other experimental approaches


  • Angiogenesis inhibitors like Bevacizumab bind and block the VEGF receptor (anti-VEGFR)
  • Thalidomide is an effective angiogenesis inhibitor
  • Protease Inhibitors aim to prevent metastasis - MMP inhibitors have shown disappointing results
  • Photodynamic therapy
  • Gene therapy e.g., restore p53 gene
  • Pro-apoptotics based on cell death pathways
  • Telomerase inhibitors
  • Cancer vaccines
  • CAR-T (Chimeric antigen receptor (CAR) T-cell therapy)
  • Immune system checkpoint inhibitors