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Department of Biological and Environmental Sciences

Cell & Molecular Biology
Dr. David A. Johnson
Biol 405    4 Credits   Spring 2017  MWF 11:45-12:50 AM   PH

Cancer: An Overview

  • Cancer: Cancer can be though of as a breakdown of the regulation of cell division, apoptosis, differentiation, and other essential functions.
    • Origin of Cancers: Cancers develop from changes that occur to a single cell and its consequential proliferation (clonality). The resulting proliferation of cells is called a malignant tumor. (A benign tumor is also a proliferation of cells, but it does not invade neighboring tissues or spread to other parts of the body.) The clonality of tumors can be shown by examining the lyonization pattern of tumor cells.
    • Classification of Cancers: Cancers can be classified according to their cell-type origin.
      • Carcinoma: This is cancer originating from epithelial cells and represents about 90% of all cancers.
      • Sarcoma: This is cancer originating from muscular or connective tissue.
      • Leukemia and Lymphoma: This is cancer originating from blood-forming cells or immune cells.

  • Characteristics of Cancer:
    • Uncontrolled Cell Proliferation
    • Loss of Density-Dependent Inhibition: Normal cells are limited in proliferation by density--availability of nutrients--and are limited by the availability of growth factors. Some cancer cells produce their own growth factors (they show autocrine growth stimulation).
    • Loss of Contact Inhibition: Contact inhibition is a characteristic of normal cells. They stop migrating and dividing when they come in contact with other cells.
    • Failure to Differentiate
    • Lack or Reduction of Apoptosis (Programmed Cell Death)
    • Metastasis: Production of proteases that digest collagen and other proteins, together with the the cancer-cell characteristics listed above, make cancer cell invasive.
    • Angiogenesis: Tumors secrete growth factors that stimulate blood vessel growth.
    • Carcinogenesis: Mutagenic agents can cause cancer (carcinogenic radiation, chemical carcinogens, tumor viruses).
      • Tests for Mutagenesis
        • Using Bacteria as Model Organisms: DNA is DNA, no matter where it is found so a chemical that is mutagenic to bacterial DNA should be mutagenic to eukaryotic DNA. Advantages: cheap and quick. Disadvantages: compared to a chemical as eaten, many chemicals are modified greatly before arriving at the DNA.
        • Using Mammalian Model Organisms: If a compound is mutagenic when fed to a mouse, it is mostly mutagenic to humans. Advantage: accurate. Disadvantage: Expensive and time consuming.
        • Ames Test--A Good Compromise: A potential mutagen is treated with a liver extract then bacteria are exposed to it.
    •  Carcinogenesis requires multiple mutational events.
      • Genetics of Cancer: At least two classes of gene alterations are needed to produce cancer.
        • Oncogenes: Changes in genes that regulate the proliferation of cells is a prerequisite to becoming a cancer cell. An oncogene stimulates the cell to divide in an unregulated fashion. These genes may enter the cell by way of a tumor virus, or may become oncogenes by mutation(s) that occurs to existing cell-cycle genes (proto-oncogenes)(the latter is more common). These mutations may be point mutations, translocations, deletions, duplications, or gene amplification.
        • Tumor Suppressor Genes: In normal cells, genes are present that would inhibit the growth of cells containing oncogenes. These are called tumor suppressor genes. These genes must be altered or deleted in order for a tumor to become malignant. (p53 is a tumor suppressor gene that works in the cells cycle halting division of abnormal cells, stimulating apoptosis, and/or stimulating DNA repair.)
        • Role of miRNAs: Increased tumor activity is often associated with the loss of some normal miRNA activity.
    • Oncogenesis:
      • Oncogenes:
        • Viruses: Some oncogenes are delivered to cells via a virus.
        • Proto-oncogenes and Oncogenes: 80% of human cancer are not induced by viruses (like some retroviruses), but arise by mutation of proto-oncogenes to oncogenes. (Retroviruses' oncogenes are most likely derived from proto-oncogenes that the virus picked up in a previous infection.)
          • A Specific Example of an Oncogene: the ras gene family: The ras family of oncogenes is the most common oncogene family in human cancers (25% of all cancers, 50% of colon carcinomas, 25% of lung carcinomas). Point mutations convert a ras proto-oncogene into an oncogene (changing one important amino acid).
            • Normal ras Gene Activity: Normal ras protein (made by the proto-oncogene) is bound to the cytosolic face of the cell membrane and may be in a inactive (bound to GDP) or active state (bound to GTP). When a growth factor, like platelet-derived growth factor (PDGF) or epidermal growth factor (EGF), is recognized by a cell, it binds to a target cell membrane receptor and the cytosolic face of the receptor is phosphorylated. This results in the recruitment of GDP-GTP exchange factor to the membrane which converts ras protein into the active (GTP-bound) form. This sets off a series of reactions that activate cell division. After this activation has occurred, the ras protein hydrolyzes its GTP to GDP and cell division is turned off.
            • Mutant ras Gene: The altered ras protein (made by the oncogene) is incapable of hydrolyzing GTP to GDP so cell division is constituitively turned on.
      • Tumor Suppressor Genes:
        • A Specific Example of a Tumor-Suppressor Gene Altered in Cancer: the p53 gene: Tumor suppressor genes inhibit cell proliferation or survival. The most frequently mutated gene in all cancer is p53, found in 50% of all cancers.
          • Normal p53 Gene Activity: The normal p53 protein controls the cell cycle, DNA repair, and apoptosis. p53 protein is always made, but usually is bound to MDM2 protein which degrades and inactivates it. When DNA is damaged, MDM2 dissociates from p53*, making it more stable and turning its activity on. (DNA damage stimulates ATM (a protein kinase) to phosphorylate MDM2 and to phosphorylate p53, both involved in MDM2 losing its ability to bind to and degrade p53.) p53's activity is as a transcription factor. This results in cell-cycle arrest and apoptosis if the DNA damage is not repaired.
          • Mutant p53 Gene: Altered p53 protein found in tumors cannot arrest the cell cycle, stimulate DNA repair, and cause apoptosis. This means that these cells survive and will have higher mutation rates. (BRCA1 and BRCA2 (common in breast and ovarian cancers) also cause a similar ignoring of cell cycle checkpoints.)
  • Recent Development in Cancer Biology: Recent approaches to understanding and treating cancer include the following.