Cancer
-genetic disease at the level of somatic cells
-associated genomic alterations include:
>>>single-nucleotide substitutions
>>>chromosome rearrangements, amplifications, and deletions
-mostly affects somatic cells with only 1% being germ line mutations
-ra
Proliferation
-fundamental property of cancer
-includes abnormal cell growth and division
Metastasis
-fundamental property of cancer
-includes defects in normal restraints that prevent cells from spreading
-genes controlling this are mutated or not expressed
-lead to spreading of cancer cells
Benign Tumors
-result from unregulated cell growth
-form a multi-cellular mass that can be removed by surgery
-cause no serious harm
-have a defined boundary
-gene expression enables change of shape
Malignant/Secondary Tumors/Metastases
-formed when tumor cells break loose
-difficult to treat
-may become life threatening
-may contain billions of cells
-may invade and grow in numerous body parts (metastasize)
Clonal Origin of Cancer Cells
-all cancer cells in primary and secondary tumors are clonal
-originated from a common ancestral cell that accumulated numerous specific mutations
-reciprocal chromosomal translocations are characteristic of many cancers such as leukemia and lymphomas
Leukemia
-cancers of the white blood cells
Lymphomas
-cancers of the lymphoid tissue
Burkitt's Lymphoma
-shows reciprocal translocations between chromosome 8 and chromosomes 2, 14, or 22
-all cancer cells arise from a single cell that is passed to progeny
Indications that Cancer is a Multi-step Process Requiring Multiple Mutations
-age-related cancer
>>>indicates that cancer develops from the accumulation of several mutagenic events in a single cell
>>>incidence of most cancers rises exponentially with age
>>>many independent mutations that occur randomly and with a low probability
Cancer's Progression of Steps
-begin with mildly abberant cells
-progress to cells that are increasingly tumorigenic and malignant
-each step in tumorigenesis appears to be the result of two or more genetic alterations that progressively release the cell from the normal controls on ce
Cancel Cells Genetic Defects
-show higher than normal rates of:
>>>mutation
>>>chromosomal abnormalities
>>>genomic instability
-fundamental defect is a derangement of the cell's ability to repair DNA damage
Genomic Instability
-manifests itself in gross defects such as:
>>>translocations
>>>anueploidy
>>>chromosome loss
>>>DNA amplification
>>>chromosomal deletions
Specific Chromosomal Defects
-used to diagnose the type and stage of the cancer
Chronic Myelogenous leukemia (CML)
-C-ABL gene on chromosome 9 is translocated into the BCR gene on chromosome 22
-structure is known as the Philadelphia chromosome
-The t (9:22) translocation is associated with CML
-BCR-ABL protein is an abnormal signal translocation molecule in CML cells
Inherited Cancers caused by defects in genes that control DNA repair (2)
1. Xeroderma Pigmentosum (XP)
2. Hereditary nonpolyposis colorectal cancer (HNPCC)
Xeroderma Pigmentosum (XP)
-extreme sensitivity to UV light and other carcinogens
-defective nucleotide excision repair of thymine dimers induced by UV light, which leads to skin cancer
Hereditary Nonpolyposis Colorectal Cancer (HNPCC)
-autosomal dominant syndrome (200-1000 affected)
-increased risk of colon, ovary, uterine, and kidney cancers
-eight genes implicated, with four involved in DNA mismatch repair
Epigenetics
-study of modifications in an organism's pattern of gene expression or phenotypic expression that are not attributable to alterations in the nucleotide sequence (mutations) of the organism's DNA
>>>DNA methylation
>>>Histone methylation and acetylation
DNA Methylation
-major alterations caused by cancer
-cancer cells are less methylated than normal cells
-promoters of some genes can be hypermethylated resulting in the release of transcription repression for some genes and repression of transcription of other genes
Histone Modification
-important epigenetic mechanism of gene regulation
-amino acids in histones can be covalently modified with addition of acetyl, methy, and phosphate groups: promoting or repressing transcription
-are disrupted in cancer cells
-genes that encode histone-mo
Genetic Affects of Cell-Cycle Regulation
-one of the fundamental abberations in all cancer cells is a loss of control over cell proliferation
-in multicellular organisms, normal cell division replaces dead and damaged tissue in strictly regulated process that involves a large number of gene prod
Cell-Cycle Control and Checkpoints
-tightly regulated
-each step must be completed before entering the next
-three distinct checkpoints monitor external signals and internal equilibrium before proceeding to the next stage
1. G1/S
2. G2/M
3. M
G1/S Checkpoint
-cell monitors size and DNA integrity
-determines whether DNA has been damaged
G2/M Checkpoint
-cell monitors DNA synthesis and damage
-psychological conditions are checked once G1/S has passed and prior to mitosis
M Checkpoint
-cell monitors spindle formation and attachment to kinetochores
-formation of spindle-fiber system and attachment of spindle fibers to the kinetochores associated with the centromeres are monitored
G0 Stage
-quiescence
-between decision to exit cell cycle and decision to reenter cell cycle
Cyclins and Cyclin-dependent Kinases (CDKs)
-regulate cell cycle progress in addition to checkpoints
-cells regulate the synthesis and destruction of cyclin proteins
-mutation or misexpression of any of the genes controlling the cell cycle can contribute to the development of cancer
-mutated genes
Control of Apoptosis
-cells halt progress through the cell cycle if DNA replication, repair, or chromosome assembly is abberant
-If DNA damage is so severe that repair is impossible, the cell may initiate genetically controlled programmed cell death to prevent cancer and elim
Two General Categories of Cancer-Causing Genes that are Mutated or Misexpressed in Cancer Cells
1. Proto-oncogenes
2. Tumor-Suppressor Genes
Proto-oncogenes
-genes whose products promote cell growth and division
-genes encode:
>>>transcription factors that stimulate expression of other genes
>>>signal transduction molecules that stimulate cell divison
>>>cell-cycle regulators move the cell through the cell cy
Oncogene
-cancer-causing gene
-mutated or abberantly expressed proto-oncogene
-gain of function mutation
-only one allele needs to mutatue or be misexpressed in order to trigger uncontrolled growth
-confer a dominant cancer phenotype
ras-Proto-oncogenes
-mutated in more than 30 percent of human tumors
-encode signal transduction molecules that are associated with the cell membrane an regulate cell growth and division
-transmit signals from the cell membrane to the nucleus, stimulating cell division
-alte
Tumor-Supressor Genes
-products regulate cell cycle checkpoints or initiate the process of apoptosis
-produce proteins that halt progress through the cell cycle in response to DNA damage or growth-suppression signals from the extracellular, tumor-suppressor genes
-mutated or i
p53 Tumor-Suppressor Gene
-mutated in more than 50 percent of all cancers
-encodes a nuclear protein that acts as a transcription factor repressing or stimulating transcription of more than 50 different genes
-p53 protein:
>>>continuously synthesized but rapidly degraded, so it is
(RB1) Retinoblastoma 1 Tumor-Supressor Gene
-loss or mutation of both alleles contributes to the development of many cancers due to unregulated progression through the cell cycle
-breast, bone, lung, and bladder cancers
Familial Retinoblastoma
-one mutated RB1 allele is inherited and has an 85 percent chance of developing retinoblastomas and an increased chance of developing other cancers
Sporadic/Somatic Retinoblastoma
-development requires two independent mutational events of RB1 within a retinal cell to inactivate both copies of the RB1 gene
Retinoblastoma protein (pRB)
-tumor-supressor proteins
-controls the G1/S cell-cycle checkpoint
-prevents passage into S phase
-activity varies throughout cell cycle, depending on phosphorylation state
-In G0: is nonphosphorylated and binds to transcription factors (E2F), inactivatin
Metastasize
-cancer cells metastasize from primary tumor by digesting components of extracellular matrix and basal lamina
>>>normally separate the body's tissue
>>>are composed of proteins and CHOs that form scaffold for tissue growth
>>>both aid in inhibiting cell m
A tumor's aggressiveness correlates positively with....
-proteolytic enzyme levels
Predisposition to Some Cancers Can Be Inherited
-most cancers result from somatic cell mutations, but 50 forms of hereditary cancer or 1-2% are known
-most inherited cancer-susceptibility alleles are not sufficient in themselves to trigger cancer development
-at least one other somatic mutation in the
Tumor Predisposition Syndromes and Gene Affected
Early-Onset Familial Breast Cancer: BRCA1
Familial Adenomatous Polyposis: APC
Familial Melanoma: CDKN2
Gorlin Syndrome: PTCH1
Hereditary Nonpolyposis Colon Cancer: MSH2, 6
Li-Fraumeni Syndrome: p53
Multiple Endocrine Neoplasia, Type 1: MEN1
Multiple Endoc
Familial Adenomatous Polyposis (FAP)
-individuals inherit one mutant copy of the APC gene whose product acts as a tumor-suppressor controlling cell-cell contact and growth inhibition
-results from one mutant copy of APC gene, chromosome 5 deletions or frameshift and point mutations
-heterozy
Viruses Contribution to Cancer in Both Humans and Animals
-15% of human cancers are associated with viruses
-second greatest risk of cancer next to tobacco smoke
Retroviruses
-RNA Virus
-can contribute to the development of cancer in animals and humans
-intergrate into the host genome as a provirus that is replicated with the host's DNA during the normal cell cycle
-can cause cancer by integrating near a proto-oncogene or inte
Viruses Associated with Human Cancers
Virus Type Virus Name Associated Cancers
DNA Epstein-Barr Burkitt's Lymphoma, B & T
Cell lymphomas
DNA Human Papilloma 16,18 Cervical Cancer
DNA Hepatitis B Hepatocellular Carcinoma
DNA Human Herpesvirus-8 Kaposi Sarcoma, lymphoma
RNA Human T lymphotrophi
Carcinogen
-any substance or even that damages DNA and causes mutations to occur in proto-oncogenes or tumor-suppressor genes
-both natural and human-made environmental agents including: chemicals, radiation, some viruses, and chronic infections
-most significant is