OCPEG Cancer

1 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I Cancer 1. Introduction Cancer is a range of diseases that is characterised by uncontrolled cell growth and division, as well as the subsequent spread of abnormal cells to surrounding tissues and other parts of the body. Many describe cancer a s a genetic disease, and indeed so, for it results from the accumulation of mutations of cancer critical genes that lead to uncontrolled cell growth and proliferation. It can also result from the loss of normal cell cycle and growth control. Understanding the multi -step development of tumors and cancers enable us to develop spec ific interventions for cancer treatment. In this part of the lecture series, you will gain an understanding of the various factors that cause cancer, the cancer critical genes and changes to them that result in cancer, as well as appreciate how cancer development is a multistep process. 2. Learning Outcomes 2 (p) Identify the causative factors, including genetic, chemical carcinogens, ionising radiation and loss of immunity, which may increase the chances of cancerous growth. 2 (q) Explain how the loss of function mutation of tumour suppressor genes, including p53, and gain in function mutation of proto-oncogenes, including ras, results in uncontrolled cell division. 2 (r) Describe the development of cancer as a multi-step process that includes accumulation of mutations, angiogenesis and metastasis. 3. References Campbell, N.A. and Reece, J.B. (2008). Biology, 8th edition. Pearson.

2 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I 4. Organisation of Lecture Content 1. Introduction 1 2. Learning Outcomes 1 3. References 2 4. Organisation of Lecture Content 2 5. Overview 3 1. Definition of Cancer 3 2. Dysregulation of Cell Cycle Checkpoints and its Link to Cancer 3 3. Types of Tumours 5 6. Molecular Basis of Cancer 5 1. Cancer as a Genetic Disease 5 2. Genes Involved in Cancer Development 6 A. Proto-oncogenes 8 B. Tumour Suppressor Gene 11 C. Gene Encoding Telomerase 13 D. Genes Encoding Proteins Involved in Angiogenesis 13 E. Genes Encoding Proteins Involved in Metastasis 14 3. Summary 15 A. Multi-step Process of Cancer 15 B. Differences Between Normal and Cancer Cells 16 7. Factors which Increase the Chance of Cancer Occurrence 17 1. Genetic Predisposition/ Heredity 17 2. Carcinogens 18 A. Chemical Carcinogens 18 B. Radiation 19 C. Viruses 21 D. Loss of Immunity 21 E. Other Factors 21

3 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I 5. Overview 5.1 Definition of Cancer  Cancer is a group of diseases characterized by o Uncontrolled cell division and o Metastasis: the s pread of abnormal cells to surrounding tissues and other parts of the body. 5.2 Dysregulation of cell cycle checkpoints and its link to cancer  Recall that you have learnt about the cell cycle checkpoints in the topic of Mitosis and Meiosis. Important points to note are summarized in the following table: Figure 1. Checkpoint controls in cell cycle. Each of the G1, G2 and M checkpoints triggers the essential processes of the cell cycle: DNA replication, mitosis and cytokinesis respectively Notes to self

4 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I  The dysregulation of cell cycle checkpoints can result in uncontrolled cell division where the rate of cell division exceeds cell death , leading to tumour formation. Checkpoint What is checked? Consequences of Dysregulation G1  Most important checkpoint to decide if cell should divide or not (G 0 phase is the non - dividing phase).  Assesses if the environmental conditions (sufficient growth factors and nutrients, absence of DNA damage and adequate cell size) are favourable for cell division. If G1 checkpoint i s defective but the cell still enters the S phase, the subsequent phases of the cell cycle (including DNA replication and mitosis) might not occur properly. G2  This checkpoint triggers the start of M phase (nuclear division)  Assesses if DNA replication is completed and cell size is adequate. If G2 checkpoint is defective but cell still enters the M phase when not all chromosomes have been replicated, the chromosome number in daughter cells would be affected. Metaphase (spindle assembly)  Last cell cycle checkpoint  Assesses if all chromosomes are attached to the mitotic spindle. If the centromeres are not attached properly to the kinetochore microtubules, entry into anaphase is prevented. If Metaphase checkpoint is defective but cell still enters anaphase, aneuploidy (extra or missing chromosome) or polyploidy (extra sets of chromosomes) would result.

5 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I 5.3 Types of tumours  The formation of tumours occurs in the d evelopment of cancer. However, having a tumour does not mean an individual has cancer.  There are 2 types of tumours, based on their pattern of growth and invasive capacity: o Benign tumour : refers to a mass of cells that keeps on dividing and does not die off readily . However, the cells grow locally and cannot spread to other regions of the body. Benign tumours are non-cancerous. o Malignant tumour : occurs when the mass of cells gain the ability to 1. Invade surrounding tissue (erode normal surrounding tissue) and 2. Metastasise (can spread to other parts of the body).  Most cancers originate from a single aberrant cell that proliferates out of control to give rise to a primary tumour whose cells eventually metastasise via the blood stream or lymphatic vessels to form secondary tumours. 6. Molecular Basis of Cancer 6.1 Cancer as a genetic disease  The vast majority of cancers are initiated by genetic mutations.  Gene mutations may be inherited: - If the mutations to cancer critical genes occur in germ line cells (reproductive cells of the body e.g. sperm and egg ), they can be passed down to the next generation. - Some people thus inherit a higher susceptibility to a single form or multiple forms of certain cancers.  Gene mutations may be acquired in an individual’s lifetime: - These mutations could result from errors that occur during cell division. They could also be caused by exposure to certain chemical substances (carcinogens) or ultraviolet rays that cause DNA damage (More details in Section 7 on Factors which Increase the Chance of Cancer Occurrence). Notes to self Notes to self

6 EJC H2 Biology T1W3 Control of Prok and Euk Genomes I  How can genetic mutations affect normal cells? o They can cause a normal cell to continue to divide. - The mutation of normal proto-oncogenes to oncogenes instructs normal cells to grow and divide excessively. As these mutated cells undergo mitosis , all the genetically identical daughter cells carry the same mutation. o They can fail to stop uncontrolled cell growth - Normal cells have the ability to stop dividing when they are in sufficient numbers in the body. However, cancer cells having a mutation in their tumour suppressor genes lose this ability and thus continue to divide. o They can have mistakes during DNA repair - Normal cells have functional DNA repair genes that control the correct repair of errors in a cell’s DNA. A mutation in the DNA repair genes will lead to errors in DNA remaining uncorrected. When cells accumulate these errors (mutations), they become cancerous.  The development of cancer i s a multi-step process . Multiple somatic mutations are required to produce all