Cancer Biology Lecture 3 PDF

CANCER BIOLOGY PROFILE OF A CANCER CELL PART-2 Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2023/2024  CANCER CANCER WHAT ARE CELLS AN...

CANCER BIOLOGY PROFILE OF A CANCER CELL PART-2 Dr. HAYTHAM MOHAMED First Semester Lecture ACADEMIC YEAR 2023/2024  CANCER CANCER WHAT ARE CELLS AND CELLS AND THE TRAITS OF CANCER CELL CYCLE APOPTOSIS CELLS? Previously Objectives 1 2 3 CANCER TUMOR MOLECULAR CELLS AND IMMUNOLOGY CHANGES IN DNA DAMAGE CANCER CELLS CANCER CELLS AND DNA DAMAGE Mutations are changes in DNA base sequence that arise either spontaneously or as a result of exposure to mutation-causing agents in the environment. Common types of DNA damage ▪ Spontaneous mutations - Depurination is the loss of the base adenine or guanine caused by spontaneous Hydrolysis. (Random interaction between DNA and Surrounding water) - Deamination, involves removal of a base’s amino group. which affects the bases C, A, and G, alters the base-pairing properties of the affected bases For example, if the base C loses its amino group by deamination, the result is an altered structure that will pair with the base A rather than with the correct base G ✓ human cell may lose thousands of adenines during the next round of DNA replication. and guanines every day and approximately 100 deaminations per day occur. (for your information only) - Mutation-causing agents ▪ Ultraviolet radiation triggers the formation of a covalent bond between two adjacent pyrimidine bases The most common types of pyrimidine dimers are thymine dimers (TT) ▪ These dimers are bulky lesions that distort the configuration of DNA and often block replication, then cells die. - REPAIR PATHWAYS ▪ Ultraviolet (UV) sterilization is a method used to disinfect air, 1- Direct Repair water, and surfaces by utilizing UV ▪ It's generally not advised to immediately switch on normal lights after using UV sterilization??? Why? The light repair ▪ Because : A photolyase enzyme recognizes the damage and binds to the thymine dimer. The enzyme absorbs visible light and uses the energy to cleave the thymine dimer. Photolyase found in many organisms except human. 2- Proofreading Repair ▪ DNA polymerase performs a proofreading function When a DNA polymerase recognizes a mispairing of bases, it removes the improperly introduced nucleotide and tries again. 3- Excision repair pathways are of two main types - The first type, called base excision repair, corrects single damaged bases in DNA. - Ex: DNA glycosylases, which Remove deaminated base - The other type of excision repair, known as nucleotide excision repair (NER), is used for removing pyrimidine dimers and other lesions in DNA. - Ex: NER endonuclease (enzyme complex)  Moon children Xeroderma pigmentosum is caused by an inherited mutation in any of seven genes coding for components of the NER system. Individuals with xeroderma pigmentosum exhibit an extremely high risk of developing skin cancer because they cannot repair the D N A damage that is caused by exposure to the ultraviolet radiation in sunlight. 4- Mismatch Repair - The mismatch repair system excises the new strand in any region containing a mismatch and then replaces the missing segment, using the base sequence of the original strand as template - The importance of mismatch repair is provided by hereditary nonpolyposis colon cancer (HNPCC) or (Lynch syndrome) an inherited disease in which people exhibit an abnormally high risk of developing colon cancer. The reason for the increased cancer risk in H NPC C is an inherited mutation in one of the genes involved in mismatch repair. 5- Postreplication Repair and the SOS Repair System - Postreplication repair occurs if DNA replication has skipped over a lesion such as a thymine dimer. Through the process of recombination, correct complementary sequence is recruited from the parental strand and inserted into the gap opposite the lesion. The new gap is filled by DNA polymerase and DNA ligase. - SOS repair is a global cellular response to DNA damage in bacteria only In the presence of a large number of unrepaired DNA mismatches and gaps, the bacteria can induce expression of about 20 genes (including lexA, recA, and uvr) whose products allow DNA replication to occur even in the presence of DNA lesions. 6- Nonhomologous End-Joining and Homologous Recombination - both used to repair Double-Strand DNA Breaks A- Nonhomologous end-joining, uses a set of proteins that bind to the ends of the two broken D N A fragments and join them together. Unfortunately, this mechanism is error- prone because it cannot prevent the loss of nucleotides from the broken ends and has no way of ensuring that the correct two D NA fragments are being joined to each other. B- Homologous recombination, that cells generally possess two copies of each chromosome; if the DNA molecule in one chromosome incurs a double-strand break, another intact copy of the chromosomal DNA is still available to serve as a template for guiding the repair of the broken chromosome ▪ Women who inherit mutations in genes called BRCA1 or BRCA2 incur a high risk for breast and ovarian cancer. The BRCA1 and BRCA2 genes produce proteins involved in the pathway that repairs double strand breaks by homologous recombination. Cancer Cells Are Genetically Unstable and Often Exhibit Gross Chromosomal Abnormalities - Cancer cells accumulate mutations at rates that can be hundreds or even thousands of times higher than normal. This condition, called genetic instability - Cancer cells are often aneuploid, which means that they possess an abnormal number of chromosomes. Aneuploidy usually involves both the loss of some chromosomes and extra copies of others. One of the first chromosomal abnormalities to be consistently observed in any type of cancer was the Philadelphia chromosome, an oddly shaped chromosome present in the cancer cells of nearly 90% of all individuals with chronic myelogenous leukemia The Philadelphia chromosome is produced by D N A breakage near the ends of chromosomes 9 and 22, followed by reciprocal exchange of D N A between the two chromosomes ▪ The translocation produces a BCR-ABL fusion gene on the shortened chromosome 22 (now called the Philadelphia chromosome). TUMOR IMMUNOLOGY The Immune Surveillance Theory Postulates that the immune system can protect against cancer. Cancer simply reflects the failure of an adequate immune response against aberrant cells. ▪ Theory Based on the facts stated that immunosuppressive drugs are acting directly to trigger the development of cancer. Immune system attack cancer cells Antigen-presenting cells that “present” antigens to cells of the immune system in a way designed to activate an immune response. The stimulated lymphocytes attack foreign antigens in two different ways. B lymphocytes, produce proteins called antibodies, Cytotoxic T lymphocytes (CTLs), bind to cells exhibiting foreign antigens on their surface and kill the targeted cells by causing them to burst. A small fraction of the total lymphocyte population consists of natural killer (NK) cells that possess the intrinsic ability (without pre stimulation by APC) to recognize and kill certain kinds of tumor cells Cancers exhibit a variety of antigenic changes. - Antigens that cannot be detected in normal cells are examples of tumor-specific antigens. - Antigens, which are present in higher concentration in a tumor but are not unique to tumors, are more accurately referred to as tumor- associated antigens.  A group of molecules called MAGE antigens are expressed in melanomas and several other cancers but not in most normal tissues. The MAGE antigens are therefore close to being “tumor- specific,” and an immune response directed against them would be expected to be reasonably selective, causing minimum damage to normal tissue. Cancer vaccines may consist of synthetic MAGE antigen peptides or whole proteins to induce an immune response Cancer cells (Various Ways of Evading the Immune System) Produce molecules that kill T lymphocytes or disrupt their ability to function. Tumors may also surround themselves with a dense layer of supporting tissue that shields them from immune attack. Some cancer cells simply divide so quickly that the immune system cannot destroy them fast enough to keep tumor growth in check. MOLECULAR CHANGES IN CANCER CELLS Cancer cells Exhibit a decrease in the number of gap junctions, which are specialized cell surface structures composed of a protein called connexin. Gap junctions play a role in cell cell communication by joining adjacent cells together in a way that allows small molecules to pass directly from one cell to another. Altered in cancer cells is their enhanced tendency to clump together when exposed in the laboratory to proteins called lectins. Cancer Cells Exhibit Cell Surface Alterations That Adhesiveness and Cell-Cell Communicationis diminished or missing entirely. Due to defects in E-cadherin Cancer Cells Produce Embryonic Proteins, Proteases, and Stimulators of Blood Vessel Growth Cancer cells tend to produce high - A great deal of effort has been expended in concentration of proteases (protein searching for molecules that are produced only by degrading enzymes) that facilitate the cancer cells and that might therefore serve as breakdown of structures that would “markers” for detecting the presence of cancer otherwise represent barriers to cancer cell movement and invasion. O n e such protein, Alpha-fetoprotein (AFP), is produced by embryonic liver cells but is Blood tests for embryonic markers such as detectable in only trace amounts in normal adults. alpha-fetoprotein and carcinoembryonic In people with liver cancer, the concentration of antigen can therefore be used to monitor alpha-fetoprotein in the blood increases the presence of certain kinds of cancer dramatically. Carcinoembryonic antigen (CEA), a protein produced in the embryonic digestive tract, and fetal hormones such as chorionic gonadotropin and placental lactogen, are also secreted by some cancers. Summary of Main Concepts Next Lecture HOW CANCERS SPREAD END OF LECTURE 3