Bcor 103 1st Edition Lecture 25 Outline of Last Lecture I. Human Genome ProjectII. Gene StudiesOutline of Current Lecture I. CancerII. Tumor Suppressors Current Lecture- Cancer: uncontrolled cell growth, found in all vertebrates (likely occurs in all multicellular organisms)- Cancer is not a single disease, but a family of diseases- Lung cancer is by far the leading cause of cancer death among men (28%), followed by prostate (9%) and colon & rectum (8%) cancers. Among women, lung (26%), breast (15%), and colon & rectum (9%) cancers are the leading causes of cancer death. - The risk of an American woman developing cancer over her lifetime is a little more than one in three. - Presently, the risk of an American man developing cancer over his lifetime is a little less than onein two. - Development of cancer requires multiple genetic changes.o Most tumors are clonal, as illustrated by x-inactivation patterns of tumors.- Key cancer problem: somatic cell evolutiono Cancer cells acquire new traits through gene activation/inactivation.- Tumor suppressor genes: function lost in cancer cellso genes that control/restrict cell growth- Oncogenes: gain of function in cancer cellso genes that promote cell growth- Aneuploidy: an abnormal number of chromosomes are a common occurrence in tumors, along with deletions, duplications and translocations.- Cancer development is a multi-stage process that requires both genetic change (mutation) and selection.- Typically <1 in 1000 tumor cells survive upon entry into the circulatory system.- Selective pressures include: hypoxia, nutrient deprivation, waste accumulation, immune response, drug therapy.- Key point: tumors are NOT composed of a homogeneous population of cancer cells.These notes represent a detailed interpretation of the professor’s lecture. GradeBuddy is best used as a supplement to your own notes, not as a substitute.- Carcinogens: induce genetic change- Some carcinogens such as aflatoxin need to be modified by cellular enzymes (often cytochrome P450 family enzymes) in order to damage DNA (metabolic activation).- Graph displays the cancer incidence in workers exposed to beta-naphthalene over time.- Tumor development is both dose and time dependent: consistent with the acquisition of multiple genetic changes.- Hiroshima/Nagasaki: peak incidence of radiation-induced leukemia occurred 5 years after use of nuclear weapons- Key concept: somatic cell evolution- Oncogenic viruses introduce new genetic material into the host cell.- Tumor induction is not part of the viral replication strategy, in nearly all cases it represents a dead end for the virus.- Infection of permissive cells results in cell lysis (death) following viral replication, therefore thereis no tumor development.- Infection of non-permissive cells, by definition, does not result in viral replication. Viral DNA may remain in host cell where it may encode proteins that contribute to tumor development.- Cell transformation does not offer the virus an advantage.- Many small DNA viruses infect non-dividing host cells. These viruses utilize the host cell DNA replication machinery to replicate their own genomes. Since the host cell DNA replication machinery is only produced in mitotic cells, these viruses encode proteins to stimulate host cell proliferation.- SV40, HPV and adenovirus induce cell division by inactivating the tumor suppressor protein Rb. These viruses also encode proteins to inactivate the tumor suppressor p53.- Inactivation of Rb results in the release of the active transcription factor E2F, which is required for the activation of genes that encode components of the DNA replication machinery, as well as genes that encode proteins that are required for entry into S phase.- Tumor promoters do not induce DNA damage, rather they promote the proliferation of cells, some of which may contain damaged DNA (mutations). Thus tumor promoters expand the population of both normal and mutant cells. The enlarged population of mutant cells increases the probability of tumor formation.- Oncogene activating mutations: promote mitosis/cell cycle progression- Tumor suppressor gene loss of function: results in loss of cell growth control, inability to control the cell