Molecular Basis for Cancer

Causes of Cancer

• Cell growth- signals that tell the cell to stop growing are mutated. Once cells grow to a certain size, they divide.
• Cell division- signals that tell the cell to stop dividing are mutated.
• Apoptosis- signals that control cell death are mutated, allowing an abnormal cell to evade death (immortalized)
• DNA repair- mutations can arise more easily in genetically unstable cells
• Growth at foreign sites- metastatic cancer occurs when cells from the primary tumor move to another part of the body and begin to grow there
• Benign cancer is contained at the originating tissue
• Malignant cancer spreads to other tissues

• One mutation is usually not enough to cause cancer
• Cancer risk increases with age because mutations accumulate over time

1. Oncogenes- ACCELERATE cancer growth
2. Ras is gene involved in cell signaling. These signals control cell growth, differentiation, and survival and mutations in Ras can disrupt these signals.
3. Myc expression leads to cell proliferation. Over-expression (gain of function) results in cells proliferating out of control
4. Tumor suppressors- STOP cancer growth
5. p53 protects genomic stability and prevents mutations. Loss of p53 function means other cancer-causing mutations are likely to arise
6. BRCA1 repairs DNA damage. Mutations in BRCA1 increase the risk of breast and ovarian cancer.

1. Mutations in protein coding sequence- resulting in hyperactive protein
2. Gene amplification- resulting in too many copies of a gene which is translated into too much protein
3. Chromosomal rearrangement- a gene is placed under the control of the wrong transcription factors or is fused to an actively transcribed gene

Warburg Effect

• Cancer cells use A LOT of glucose compared to the surrounding, non-cancerous tissue cells
• Aerobic glycolysis- the glucose was metabolized into lactate even in the presence of oxygen
• Cancer cells survived in the absence of oxygen as well

1. Oxidative phosphorylation: in the PRESENCE of oxygen, 1 glucose---> 36 ATP
2. Anaerobic respiration: in the ABSENCE of oxygen, 1 glucose ---> 2 ATP

• Perhaps the cancer cells need other by-products obtained from anaerobic respiration
• Perhaps cancer cells use anaerobic respiration because it is much faster than oxidative phosphorylation
• Perhaps the mitochondria is damaged and the cancer cells CAN'T use oxidative phosphoylation
• Ongoing research.....

• Evading growth suppressors
• Activating invasion and metastasis machinery
• Allowing replicative immortality
• Inducing angiogenesis
• Resisting death signals
• Sustaining proliferation

• Cancer hijacks normal cellular processes of cell division!
• Cell division is controlled by cyclins and cyclin-dependent kinases (CDKs)
• Cyclins bind CDKs in order to activate them
• Activated CDKs phosphorylate other proteins required in cell cycle progression
• Mutation or over activation of CDKs or cyclins allows cancer to grow uncontrollably
• Gain of function mutations in proto-oncogenes leads to a deregulation in the cell cycle
• E.g. mutations in the epidermal growth factor receptor (EGFR)

• Tumor suppressors are proteins that inhibit the cell cycle
• E.g. p53 detects DNA damage
• E.g. BRAC1 fixes double stranded breaks
• Loss of function in tumor suppressors leads to familial heredity of cancer = 2 hit hypothesis
• e.g. first mutation occurs randomly in the germline of the parent (= first hit) $$$\to$only 1 functioning gene in offspring... random second hit in a single cell = no functional copies $\to$cancer

• miRNAs can act to either promote or inhibit cancer progression depending on what gene mRNA they target
• Oncomirs = miRNAs with a role in cancer progression

Cancer Treatments

1. Surgery- physically remove the cancer cells
2. BUT it is difficult to remove every single cancer cell. Only one needs to escape surgery for cancer to recur
3. Radiation- severely damage the DNA of the cancer cells
4. BUT radiation affects normal cells too
5. Chemotherapy- severely damage the DNA of cancer cells OR interfere with mitosis OR interfere with replication
6. BUT chemotherapy affects normal cells too
7. BUT not every cancer can be treated with the same chemotherapy. Different mutations in different cells= different diseases

• Cancer cells in the same tumor are not necessarily identical
• Cancer cells can evolve over time

• Increase specificity: Use antibody-drug conjugates or teach immune cells to target cancer cells
• Detect cancer early: It is easier to get rid of 10 cells than it is to get rid of 1,000,000,000 cells
• Combination therapies: two therapies working together to eliminate only cancer cells
• Understanding cancer genetics: if we understand which genetic mutations cause cancer, we can detect cancer risks earlier
• Prevention: learn what causes cancer so we can avoid it (e.g. smoking, UV rays from the sun, chemical additives in food, etc.)