CANCER GENES AND PATHWAYS : CANCER GENES AND PATHWAYS Edward Laurence L. Opena
Master of Science In Biology 1
Mindanao State University – Iligan Institute of Technology What is Cancer? : What is Cancer? Medical Term: Malignant Neoplasm
Is a class of diseases in which a group of cells display its three malignant properties:
a. uncontrolled growth – division beyond the normal limit
b. invasion – invasion on and destruction of adjacent tissues
c. metastasis – spread to other locations in the body via lymph or blood Slide 5: Those three malignant properties of cancers differentiate them from benign tumors, which are self-limited, do not metastasize or invade
Most cancers form a tumor, but some do not (leukemia)
Cancer may affect people at all ages, even fetuses, but risk for most varieties increases with age. Cancer causes about 13% of all deaths
The branch of medicine concerned with the study, diagnosis, treatment, and prevention of cancer is oncology. What Causes Cancers? : What Causes Cancers? Nearly all cancers are caused by abnormalities in the genetic materials of the transformed cells. These abnormalities may be due to the effects of carcinogens:
- tobacco smoke
- radiation (ionizing radiation: radon gas; UV, X-rays and gamma rays
- chemicals (mutagens, carcinogens)
- infectious agents (oncoviruses: human papillomavirus, hepatitis B and hepatitis C virus, Epstein-Barr virus, and human T-lymphotropic virus)
- Hormonal imbalances
- Immune system dysfunction
- Heredity Slide 7: Other cancer-promoting genetic abnormalities may be randomly acquired through errors in DNA replication, or are inherited, and thus present in all cells from birth.
The heritability of cancers are usually affected by complex interactions between carcinogens and the host's genome
New aspects of the genetics of cancer pathogenesis, such as DNA methylation, and microRNAs are increasingly recognized as important. Two General Classes of Genes in Cancers : Two General Classes of Genes in Cancers Cancer-promoting oncogenes
- typically activated in cancer cells, giving those cells new properties, such as hyperactive growth and division, protection against programmed cell death, loss of respect for normal tissue boundaries, and the ability to become established in diverse tissue environments. Slide 9: WHAT ARE ONCOGENES?
-promote cell growth, produce hormones that encourage mitosis
-some oncogenes are part of the transduction system, or serve as the cells’ receptors, thus controlling hormonal sensitivity.
- Oncogenes often produce mitogens, or are involved in transcription of DNA in protein synthesis, which creates the proteins and enzymes responsible for producing the products and biochemicals cells use and interact with. Slide 11: Mutated proto-oncogenes, which are the quiescent counter part of oncogenes, modifies their expression and function, increase protein product. Thus upsets the normal balance of cell cycle and makes an uncontrolled cell proliferation possible.
The chance of cancer cannot be reduced by removing proto-oncogenes from the genome, even if this were possible, as they are critical for growth, repair and homeostasis of the organism. It is only when they become mutated that the signals for growth become excessive.
One of the first oncogenes to be defined in cancer research is the ras oncogene. Mutations in the Ras family of proto-oncogenes (comprising H-Ras, N-Ras and K-Ras) are very common, being found in 20% to 30% of all human tumours Slide 12: B. Tumor suppressor genes
- inactivated in cancer cells, resulting in the loss of normal functions in those cells, such as accurate DNA replication, control over the cell cycle, orientation and adhesion within tissues, and interaction with protective cells of the immune system. Slide 13: WHAT ARE TUMOR SUPPRESSOR GENES?
- code for anti-proliferation signals and proteins that suppress mitosis and cell growth.
- are transcription factors that are activated by cellular stress or DNA damage. Often DNA damage will cause the presence of free-floating genetic material as well as other signs, and will trigger enzymes and pathways which lead to the activation of tumor suppressor genes
- The functions of such genes is to arrest the progression of the cell cycle in order to carry out DNA repair, preventing mutations from being passed on to daughter cells. Slide 14: The p53 protein, one of the most important studied tumor suppressor genes, is a transcription factor activated by many cellular stressors including hypoxia and ultraviolet radiation damage.
Despite nearly half of all cancers possibly involving alterations in p53, its tumor suppressor function is poorly understood. p53 clearly has two functions: one a nuclear role as a transcription factor, and the other a cytoplasmic role in regulating the cell cycle, cell division, and apoptosis. Slide 15: The Warburg hypothesis is the preferential use of glycolysis for energy to sustain cancer growth. p53 has been shown to regulate the shift from the respiratory to the glycolytic pathway.
However, a mutation can damage the tumor suppressor gene itself, or the signal pathway which activates it, "switching it off". The invariable consequence of this is that DNA repair is hindered or inhibited: DNA damage accumulates without repair, inevitably leading to cancer. General Categories of Cancers : General Categories of Cancers Carcinoma: Malignant tumors derived from epithelial cells. This group represents the most common cancers, including the common forms of breast, prostate, lung and colon cancer.
Sarcoma: Malignant tumors derived from connective tissue, or mesenchymal cells.
Lymphoma and leukemia: Malignancies derived from hematopoietic (blood-forming) cells
Germ cell tumor: Tumors derived from totipotent cells. In adults most often found in the testicle and ovary; in fetuses, babies, and young children most often found on the body midline, particularly at the tip of the tailbone; in horses most often found at the poll (base of the skull).
Blastic tumor or blastoma: A tumor (usually malignant) which resembles an immature or embryonic tissue. Many of these tumors are most common in children. How do Cancers form? : How do Cancers form? ALTERATION OF GENE SEQUENCE FOR
CELL GROWTH AND DIFFERENTIATION GAIN OR LOSS OF AN ENTIRE CHROMOSOME (ANEUPLOIDY; DOWN’S SYNDROME) [LARGE SCALE MUTATION] INSERTION OR DELETION OF NUCLEOTIDES (SMALL SCALE MUTATION) HIGH-LEVEL EXPRESSIONS OF ONCOGENES SWITCHING OFF OF TUMOR-SUPPRESSOR GENES CANCER CELLS Slide 18: LARGE SCALE MUTATION
-involve the deletion or gain of a portion of a chromosome
-Genomic amplification occurs when a cell gains many copies (often 20 or more) of a small chromosomal locus, usually containing one or more oncogenes and adjacent genetic material
-Translocation occurs when two separate chromosomal regions become abnormally fused, often at a characteristic location.
-A well-known example of this is the Philadelphia chromosome, or translocation of chromosomes 9 and 22, which occurs in chronic myelogenous leukemia, and results in production of the BCR-abl fusion protein, an oncogenic tyrosine kinase. Slide 19: SMALL SCALE MUTATION
-include point mutations, deletions, and insertions, which may occur in the promoter of a gene and affect its expression, or may occur in the gene's coding sequence and alter the function or stability of its protein product.
-Disruption of a single gene may also result from integration of genomic material from a DNA virus or retrovirus, and such an event may also result in the expression of viral oncogenes in the affected cell and its descendants. The Epigenetics of Cancer : The Epigenetics of Cancer Epigenetics is the study of the regulation of gene expression through chemical, non-mutational changes in DNA structure
The theory of epigenetics in cancer pathogenesis is that non-mutational changes to DNA can lead to alterations in gene expression.
Because of DNA methylation, oncogenes are silent
Loss of that methylation can induce the aberrant expression of oncogenes, leading to cancer pathogenesis. Biological properties of cancer cells : Biological properties of cancer cells Acquisition of self-sufficiency in growth signals, leading to unchecked growth.
Loss of sensitivity to anti-growth signals, also leading to unchecked growth.
Loss of capacity for apoptosis, in order to allow growth despite genetic errors and external anti-growth signals.
Loss of capacity for senescence, leading to limitless replicative potential (immortality)
Acquisition of sustained angiogenesis, allowing the tumor to grow beyond the limitations of passive nutrient diffusion.
Acquisition of ability to invade neighbouring tissues, the defining property of invasive carcinoma.
Acquisition of ability to build metastases at distant sites, the classical property of malignant tumors (carcinomas or others).