BIO372 : Cancer : Biology of Cancer : Lesson

I. How cancer arises

1. Introduction
   • The human body contains 30 trillion cells
   • Normal cells are interdependent and regulate one another's activities
   • Cancer cells follow an independent agenda and can migrate to different locations
     • Lethal when they disrupt the functioning of tissues and organs
     • Descend from a cell that was transformed years earlier
     • Transformation results through the accumulation of mutations in certain classes of genes
   • Proto-oncogenes encourage cellular growth
     • Mutation results in too much growth stimulating protein
   • Tumor suppressor gene inhibits cell growth
     • Mutation results in a loss of suppressor proteins so no brakes on cell division

2. Signaling systems go awry
   • Cell-to-cell signaling
     • One cell secretes a growth factor (a protein)
     • Growth factor binds to a receptor on a nearby cell, specific to that protein
     • Receptor is a transmembrane molecule that projects into the cell's cytoplasm
     • Binding sends a signal to cytoplasmic protein which is relayed to the cell's nucleus where transcription factors activate the cell to begin its growth cycle
   • Cancer
     • Oncogenes in cancer cells produce excessive amounts of growth factor
     • Oncogenes for receptors send proliferative signals for cell replication when no growth factor is present, e.g., Erb-B2 receptors in breast cancer
     • Oncogenes (ras family) send growth signals through the cytoplasm spontaneously - found in 25% of human tumors
     • Oncogenes (Myc family) increase activity of transcription factors, especially in malignancies of blood-forming tissues
     • Understanding the signaling process presents possibilities for anticancer therapies

3. Tumor supressors stop working
   • In normal cells, growth is inhibited by signals from neighboring cells
   • Tumor cells do not respond to inhibitors
     • Transforming growth factor beta (TGF-ß) blocked in some colon cancer cells by inactivating a gene encoding a surface receptor
     • DPC4 gene inactivated by some pancreatic cancers
     • p15 gene, which shuts down the cell growth cycle after a signal from TGF-ß, is discarded by various cancers
     • NF-1 gene normally prevents the Ras protein from signaling
   • Possible therapy in replacing a tumor suppressor gene in cancer cells

4. Cell cycle clock
   • Cell cycle
     • G1 phase occurs often previous mitosis: cell increases in size and prepares to duplicate its DNA
     • D-type cyclins bind to CDK's 4 or 6 and form a complex
       • p15 and p16 inhibitory proteins block CDK's from binding with cyclin
       • p21 inhibitory protein can block CDK's at any point in the cell cycle; it is under control of p53 tumor suppressor protein
     • Complex acts on pRB (master brake) releasing transcription factors
   • Cancer
     • Excesses of cyclin D and E produced in breast cancer cells
     • p16 is lost in melanoma
     • p53 is non-functional in half of all human tumors
     • pRB and p53 proteins are frequently disabled in cervical cancers triggered by infection with papillomavirus
     • Possible therapy if cyclins and CDK's can be blocked

5. Fail-safe system
   • Apoptosis (ah'-puh-toe'-sis): normal programmed death of a cell when it is no longer needed (as in embryological development) or it is damaged
     • p53 protein helps to trigger apoptosis, but is inactivated in tumors
     • Bcl-2 protein, made excessively by cancer cells, wards off apoptosis
     • Cancer cells injured by radiation or chemotherapy resist death
   • Limit to the number of mitotic divisions
     • Normal cells become senescent after 50-60 mitotic divisions
     • Cells with mutations in either pRB or p53 continue to divide until a crisis stage at which they die
     • Some cells escape crisis and divide immortally forever
     • Mechanism
       • DNA segments at ends of chromosome (telomeres) protect chromosomes from damage but shorten a bit at each mitosis
       • When short enough, cells enter senescence or crisis
       • Cancerous cells produce an enzyme, telomerase, which replaces lost telomeric segments
       • Possible therapy in blocking telomerase

6. Early cancer
   • Normally takes decades for an incipient tumor to collect all the mutations required for malignant growth
   • Accelerated tumor formation
     • Inheritance of a mutant cancer-causing gene
       • All body cells begin life with the mutation
       • Mutation is passed to future generations in the same family
       • Examples: defective tumor suppressor gene APC in colon cancer; defective pRB in retinoblastoma and osteosarcoma; defective p53; familial breast cancers
     • Defects in the enzymes that normally correct errors in the DNA duplication process
       • Examples: colon cancer, xeroderma pigmentosum, defective ATM gene
     • Possible therapy in DNA analysis to pinpoint defects

7. Steps in cancer development beyond cell proliferation that invite investigation
   • Genes to attract blood vessels to tumors for nourishment
   • Genes for tumor cells to invade nearby tissues
   • Genes for tumor cells to metastasize
   • Genes for malignancies are genes for embryonic development

1. Introduction
   • Normal cells become differentiated to specialized types (nerve, muscle, liver) and are linked with other cells in a tissue
   • Cancer cells revert to an undifferentiated form and lose functions of the mature cell
   • Metastatic cancer cells gain the ability to migrate to new sites, grow, and crowd out normal cells and vital organs

2. Carcinogenesis
   • Cellular events that transform a cell to cancerous can take more than ten years
   • Regulation of the number of cells in normal tissue
     • Genetic mechanism of programmed cell death (apoptosis)
     • New cells originate by mitosis from stem cells, then differentiate into the mature cell type and replace lost cells
     • Cell longevity varies
       • Nerve and muscle cells are long-lived
       • Skin, epithelial lining of gut, blood cells live for a few days
     • Balance between cell division and apoptosis
   • Angiogenesis
     • Growing cell mass sends signals to other cells which induce surrounding connective tissue and vascular cells to grow blood vessels to the cell mass
     • Possibly the lack of oxygen in the interior of the cell mass initiates the signals
     • Blood vessels supply oxygen and nutrients and provide an escape route for migrating cancer cells
     • Connective tissue and vascular cells produce signals which stimulate the growth and motility of the cancer cells

3. Cells connect to form a tissue
   • Adherence junction
     • Protein E-cadherin spans the cell membrane from inside to outside
       • External portion forms interlocking bonds with E-cadherin on neighboring cells
       • Internal portion hooks to the cell's cytoskeleton with protein catenins
       Hypotheses for breakdown of the adherence junction
       • Hypothesis 1: Mutation in E-cadherin gene prevents proper connections
       • Hypothesis 2: Decrease in number of E-cadherin molecules on the cell surface
       • Hypothesis 3: Absent or nonfunctioning catenin linking proteins
   • Integrin
     • Protein spans the cell membrane from inside to outside
       • External portion forms connections with connective tissue proteins outside the cell
       • Internal portion hooks to the cell's cytoskeleton
     • Integrin of cancer cells, rather than locking the cells in place, latch onto proteins in the connective tissue matrix and pull the cells through

4. Passing through walls
   • Cancer cells begin as differentiated, mature cell types with a skeletal structure for sedentary activity
   • A cancer cell has an altered structure, reverting to an undifferentiated form resembling cells in the early stages of embryonic development
   • Penetration of the connective tissue wall
     • Cancer cells secrete proteases which dissolve the connective tissue matrix and allow them to pass through
     • Matrix metalloproteinases (MMP), e.g., cathepsin-B, is normally sequestered inside the cell's lysosomes; in cancer cells, it is bound to the cell surface

5. Cancer cell in circulation
   • Possible mechanical destruction in transit
   • Possible detection and destruction by macrophages or killer T cells
   • Survival chance increased if cancer cells cluster together or surround themselves with blood platelets
   • Selection of a new tissue
     • Specificity is dependent on compatibility of cell surface molecules on cancer cell and on the new tissue, probably by an interaction between a carbohydrate on the surface of the cancer cell and selection on the endothelial cell
   • Cancer cell migrates through the blood vessel wall, dissolves the connective matrix with proteases, enters the new tissue, and starts a new tumor

6. Anticancer strategies
   • Surgical removal of a tumor: some cancer cells may remain or have migrated
     • Radiation induces cancer cells to undergo apoptosis
     • Chemotherapy to curtail cell division and proliferation
       • Normal cells with high turnover rates, such as skin, hair and blood cells, are also curtailed
   • Boost patient's immune system to recognize and eliminate cancer cells
     • Cancer cells can secrete immunosuppressive messenger molecules as well as eliminate cytokines and proteases released by lymphocytes
     • Some cancer cells express the Fas molecule which binds to the FasL receptor on immune cells and causes the immune cell to undergo apoptosis
   • Cause cancer cells to kill themselves by enhancing expression of both Fas and FasL on the cancer cells
   • Prevent angiogenesis at the tumor site with angiostatin and endostatin
   • Inhibit the growth stimulating proteins of mutated ras genes
   • Restore the function of growth-inhibiting genes
   • Halt metastasis
     • Stimulate or replace adhesion molecules to hold the cancer cells in place
     • Inhibit the proteases that dissolve connective tissue matrix

7. Diet and cancer
   • Some dietary nutrients might protect against cancer, e.g., vitamins E and C, selenium, wine and phytochemicals
   • Fatty acids
     • Omega-3 polyunsaturated fatty acids (in salmon and mackerel) restrict cellular proliferation but inhibit stroma formation that the body uses to encapsulate and restrict a tumor
     • Omega-6 PUFA's (from plants)seem to promote tumor growth

III. Angiogenesis inhibitors

1. Generalizations
   • 1.5 million people in the U.S. are diagnosed with malignancies each year
   • Half of all cancer patients survive five years
   • Surgery is the most potent weapon against cancer, drug treatment accounts for less than 10% of all recoveries

2. Blood vessel proliferation
   • Healthy cells constantly regulate the growth of nearby blood vessels with chemical messengers
     • Blood vessel cells have receptors for both inducers and inhibitors
   • If cancer cells cease sending inhibitors, nearby vessels form capillaries to the cancer cells
     • MMP's bore into the tumor and connect to the blood vessels

3. Disrupting angiogenesis
   • Old drugs: Thalidomide and TNP-470; side-effects
   • Engineered drugs: antibody that blocks VEGF, block MMP's
   • Tumor produced inhibitors: endostatin and angiostatin
     • Blocked angiogenesis in mice and tumors shrunk and disappeared
     • Probably be combined with other forms of treatment in humans
     • Advantage: not necessary to eradicate all tumor cells if block their blood supply

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