which cell divide in an uncontrolled, relatively autonomous fashion, leading to a progressive increase in the number of dividing cells. The resulting mass of growing tissue is called a tumor or neoplasm. Cancers can originate in almost any organ. They are grouped depending on the cell type:
1. Carcinomas (most prominent @90%) arise from epithelial cells (from external and internal body surfaces). 2. Sarcomas arise from supporting tissues (bone, cartilage, fat, muscle etc.) 3. Lymphomas and leukemia arise from cells of blood and lymphatic origin. Key properties of cancer cells:
1. The ability of cells to proliferate in an uncontrolled fashion and 2. The ability to spread through the body. It is the combination of these actions that makes cancers dangerous. Tumors are produced by uncontrolled cell proliferation in which the balance between cell division and cell differentiation is disrupted Comparison of normal and tumor growth in the epithelium of the skin. The basal layer of epithelial cells grow more than the surrounding cells to form a tumor Based on differences in their growth patterns, tumors are classified as either benign or malignant.
Benign tumor grows in a confined local area and is rarely dangerous whereas malignant tumor is capable of invading surrounding tissues, entering blood stream and spreading to distant parts of the body which make it a serious health hazard. Benign malignant Cancer cell proliferation is anchorage- independent and insensitive to population density
Normal cell dont grow well in liquid or semi solid medium and require a supporting surface to grow in culture.
Cancer cells can grow well in liquid or semi-solid media therefore exhibit anchorage independent growth Tumor cells Monolayer stage Piling up on top of each other A B Tumor cell are insensitive to population density In culture, most normal cells divide until a monolayer is formed. Cancer cells "pile up". Cancer cells are immortalized by mechanism that maintain telomere length Normal cell divide about 50-60 times when placed in culture, then stop dividing. Whereas HeLa cell dividing more than 18,000 times with no sign of stop Cancer cell Normal cell Telomerase enzyme add DNA sequences at the end of the chromosome of tumor cells thus maintaining the telomere length Abnormalities in signaling pathway, cell cycle controls and apoptosis contribute to uncontrolled proliferation
If the normal cell grown under suboptimal conditions (insufficient growth factors, inadequate nutrients), the cells become arrested at the restriction point (G1 into S phase) and stop dividing.
In compare cancer cells continue to proliferate even in the extreme adverse condition rather than arresting at G1 phase. How cancer spreads? Angiogenesis is growth of blood vessels in the surrounding tissues, required for tumors to grow beyond a tiny localized clump of cells.
Tumor cell release signaling molecules that trigger Angiogenesis includes VEGF and FGF. Angiogenesis Experiment illustrating the requirement for Angiogenesis Molecules that regulate angiogenesis includes both activators and inhibitors. Activators Inhibitors VEGF (vascular endothelial growth factor) Angiostatin FGF (fibroblast growth factor) Endostatin Thrombospondin Spreading of cancer by invasion and metastasis is a complex and multistep process
1. Cancer cells migrate and penetrate into adjacent tissues and vessels. 2. Transport via circulatory system and 3. Reinvasion and growth at a distant sites to form a tumor. Invasion and Metastasis Invasion and metastasis processes require changes in cell adhesion molecule (E- cadherin), motility (signaling molecules as chemo-attractants) and the production of proteases that degrade protein-based physical barriers to cell movement. What Causes Cancer? Causes of Cancer
Chemicals Diet and obesity Infection Radiation Heredity Physical agents Hormones
Factors Believed to Contribute to Global Causes of Cancer Cigarette Smoking Tobacco smoking is associated with many forms of cancer, and causes 90% of lung cancer in US Carcinogens Ames test to identify potential carcinogens Viral Factors Herpes-related viruses may be involved in the development of leukemia, Hodgkins disease, cervical cancer, and Burkitts lymphoma Epstein-Barr virus, associated with mononucleosis, may contribute to cancer Human papillomavirus (HPV), virus that causes genital warts, has been linked to cervical cancer Helicobacter pylori causes ulcers which are a major factor in the development of stomach cancer Oncogene and Proto-oncogene Oncogenes are a gene whose presence can trigger the development of cancer.
Some oncogene are introduced by cancer causing virus, whereas other arise by mutation from normal cellular gene.
Either case gene product stimulate excess cell proliferation. Oncogenes arise by mutation from normal cellular genes called proto-oncogenes.
Proto-oncogenes are not harmful genes, they are normal cellular genes that play role in regulation of cell growth and survival.
They become oncogene when their structure are disrupted by mutation, the mutant form cause cancer. Mutation that convert proto-oncogenes into oncogenes are created by several mechanism:
1. Point Mutation 2. Gene Amplification 3. Chromosomal translocation 4. Local DNA rearrangements 5. Insertional Mutagenesis Most oncogenes codes for components for growth signaling pathway
1. Growth factors 2. Receptors 3. Plasma membrane GTP-binding proteins 4. Non-receptor Protein kinases 5. Transcription factors 6. Cell cycle or cell death regulators
Tumor Suppressor genes Fusion cancer cell with normal cell Tumor suppressor genes are genes whose loss or inactivation can lead to cancer
The RB tumor suppressor gene was discovered by studying families with hereditary retinoblastoma G1 S phase Disruption of RB protein removes restrain mechanism and open door to uncontrolled proliferation The p53 tumor suppressor gene is the most frequently mutated gene in human cancer The DNA damage checkpoint is regulated by p53, "the Guardian of the Genome"!
The role of p53 is to protect cells from the effects of DNA damage. What will happen if p53 gene get disrupted? Upon inactivation of p53 pathway results cancer development by allowing the survival and reproduction of cells containing damaged DNA Both Rb protein and p53 protein are the target for cancer causing virus Human papillomavirus (HPV)