Cellular and Molecular Biology Topics                                                                

Cancer

Terminology

A benign tumor is a clonal overgrowth of cells that grows autonomously but does not metastasize. A malignant tumor is a clonal overgrowth of cells that grows autonomously, lacks many differentiated properties and has metastasized.

Cancer is a group of diseases characterized by clonality, autonomy, anaplasia and metastasis. Clonality refers to the fact that cancer arises from genetic changes in a single cell which proliferates and forms clones of malignant cells. Autonomy means that cell growth is not properly regulated by the normal biochemical and physiological influences in the environment. Anaplasia means that normal, coordinated cell differentiation is absent. Metastasis is the capacity of cancer cells for discontinuous growth and dissemination to other parts of the body.

Carcinoma refers to any of various types of cancerous tumors that form in the epithelial tissue, the tissue forming the outer layer of the body surface and lining the digestive track and the hollow structures. Examples of carcinomas include breast, lung and prostate cancers. Sarcomas are cancerous tumors that form in non-epithelial tissues. Examples of sarcoma are melanomas and bone cancer. Leukemia is uncontrolled proliferation of one kind of leukocyte.

Cancer may arise from either genetic or epigenic changes. Genetic changes are alterations in the cell’s DNA sequence: point mutations, deletions, translocations or amplifications. Such changes result in either dominant (gain of function) or recessive (loss of function) effects. Epigenetic changes arise from a change in the pattern of gene expression without a change in the DNA sequence. Enzymatic DNA methylation at the C-5 position of cytosine residues can affect epigenic inheritance by altering the expression of genes and by transmission of DNA methylation patterns through cell division.

The process of carcinogenesis has three stages: initiation, promotion and progression. Initiation involves a genetic change that turns a normal cell into an initiated cell. Promotion refers to the clonal expansion of the initiated cell into a preneoplastic lesion. Epigenic changes play a role in the promotion process. Progression occurs as the clonal cell start to have genetic changes and become a metastatic malignant tumor.

The inheritance of some defective gene will affects the probability of developing cancer. Such genes include those that control the cell cycle, DNA repair mechanisms and carcinogen metabolism. Inheritance of defective cell cycle genes will increase the probability of developing cancer 103-104 times fold. Inheritance of defective metabolic enzyme genes will increase the probability of developing cancer only 2-10 fold. There is an inverse correlation between how much increased cancer probability a mutated gene will confer and the occurrence of such genes in the general population. The most damaging mutations in cell cycle genes occur at a very low rate, while the mutated metabolic genes occur more often.

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Tumor Evolution

Development of cancer is a multistep process involving mutation and selection for cells with a progressively increasing capacity for proliferation, survival, invasion and metastasis. The first step, known as initiation, results from genetic alteration of a single cell to an abnormal phenotype. Since cancer may arise from a mutation in a single cell the probability of getting cancer increases with age because of the accumulation of possible mutation events.

If the mutation induces disregulation of the cell cycle, proliferation of a clonal cell population from this original cell occurs, a process known as progression. As progression unfolds, additional mutations may develop that confer a selective advantage to the cell such that its descendents become the dominant population. Such clonal selection continues throughout tumor development, so the tumor becomes more rapid-growing and increasingly malignant.

Although a tumor arises form clonal growth of an initiated cell, the rapid unregulated growth will lead to genetic variation in the tumor cell population. Eventually, a genetic change will arise that will give that cell a growth advantage over the rest. This one cell will proliferate more rapidly, while others may stop proliferating. Therefore, if a tumor is sequentially sliced and analyzed, regions of sequential clonal expansion will be seen as well as regions of high diversity, were a balance of mitosis and cell death occurs.

Metastasis is when cancer cells develop the capacity for discontinuous growth and dissemination to other parts of the body. It starts by invading adjacent tissue, using metalloproteases to destroy the basal membrane. Tumor cells grow as microcylinders or “microcuffs” (?). After rapid proliferation without proper blood supply, hypoxia will occur. Without a blood supply, the tumor will become hypoxic and necrotic. Therefore the growth of new blood vessels throughout the tumor facilitates further tumor growth by providing oxygen and nutrients.

As tumor cells reach the vasculature, angiogenesis is induced. Angiogenesis is the recruitment of blood vessels and neovascularization, driven by the secretion of peptides normally involved in wound repair: vascular endothelial growth factor (VEGF) and platelet derived growth factor (PDGF). Hypoxia will induce dimmerization of HIF1a with HIF1b, which bind to hypoxia response elements (HRE) that induce VEGF production.

Once they have access to blood vessels, tumor cells can migrate to distant tissue. Tumor cells that reach other tissues will continue to proliferate, sometimes aided by local growth factors. Angiogenic switch is the expansion of a tumor to a detectable size, local bleeding and metastasis (?).

Angiogenesis may occur by a variety of mechanisms: (1) avascular in situ recruitment of the blood supply by stimulating neovascularization, (2) tumor induction of stromal tissue elements to produce angiogenic factor, (3) circulating endothelial cell precursors from blood marrow incorporate into tumor site, (4) preexisting vessels coopted by tumor.

The primary tumor will secrete antiangiogenic factors in addition to the angiogenic factors. Secretion of antiangiogenic peptides includes angiostatin (plasminogen cleavage product) and endostatin (type XVII collagen cleavage product). At the primary tumor site, the angiogenic factor levels will be higher than antiangogenic factor levels. But antiangiogenic factors have a longer serum half-life than angiogenic factors. Therefore antiangiogenic factors will suppress metastatic growth at remote tissues.

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Tumor Phenotype

Cancer cells display abnormalities in the mechanisms that regulate normal cell proliferation, differentiation, and survival. Autonomous growth refers to the fact that cancer cells do not require outside signals to grow and proliferate. Normal cells growth is controlled by growth factors from other cells, by physical interactions from with other cells and by internal mechanisms of the cell cycle that identify and repair damage before attempting cell division. A cancer cell may be producing its own growth factors, or have a mutated, constitutively active growth factor receptor. Alternatively, a cytosolic signaling molecule of the growth factor receptor signaling pathway may be constitutively active. Several types of proteins that control the cell cycle may also be mutated. Positive regulators of the cell cycle can be constitutively active, or negative regulators can be mutated in such a way as to impair their function.

Normal cells have fibronectin as a surface cell protein, while tumorigenic do not (“tumor antigen”?) . Normal cells do not grow on soft agar (require anchoring) and their growth is inhibited by contact of adjacent cells. Tumorigenic cells can grow in soft agar (do not require anchoring) and grow on top of each other forming foci when space is limited. Normal cells have a structured cytoskeleton, while that of tumor cells is disorganized and there is a decreased amount of cytoskeletal proteins. Normal cell metabolism relays mostly on glycolysis and the TCA cycle, while tumor cells use glycolysis but also lactic acid anaerobic metabolism (Warburg effect). Since normal cell differentiation is absent, tumor cells have immature/embryonic gene expression and often more than 2N.

Normal cells depend on growth factors to proliferate while tumorigenic cells behave independently from growth factors. Tumor cells do not respond to normal biochemical and physiological influences through the autocrine, paracrine and endocrine routes.Autocrine signaling occurs when the cell signals to itself through a molecule it produces. Autocrine signaling can occur solely within the cytoplasm of the cell (intracrine) or by a secreted molecule that interacts with receptors on the surface of the same cell. Paracrine signaling occurs when molecules diffuse into an area and interact with receptors on nearby cells. This includes release of cytokines that cause an inflammatory response in the area or release of neurotransmitters at synapses of the nervous system. Endocrine signaling involves molecules secreted into the blood and carried to the cells they act upon.

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Cellular Proto-Oncogenes

Cellular proto-oncogenes are normal cellular genes that play a fundamental role in regulation of cell growth and differentiation. They are highly conserved throughout evolution and are subdivided into 4 families: growth factors or their receptors, stimulatory signal proteins, transcription factors that activate growth-promoting genes and other kinds of molecules related to the cell cycle. Mutated proto-oncogenes are known as oncogenes.

Examples of genes for growth factors or their receptors are erb-B2 and RET. Erb-B2, also known as HER-2 or neu, codes for a growth factor receptor involved in breast, salivary gland and ovarian cancer. RET is a growth factor receptor involved in thyroid cancer. Examples of genes for stimulatory signaling proteins include Ki-ras and c-abl. Ki-ras is a GTPase involved in lung, ovarian, colon and pancreatic cancers. C-abl is a non-receptor tyrosine kinase. An example of a gene for transcription factors that activate growth-promoting genes is N-myc, which is involved in neuroblastoma and glioblastoma. Examples of genes for other kinds of molecules are Bcl-2, Bcl-1 and Mdm2. Bcl-2 is a protein that normaly bocks apoptosis, and is involved in follicular B cell lymphoma. Bcl-1, also known as Prad1, codes for cyclin D1, and is involved in breast, head and neck cancers. Mdm2 is an antagonist of the p53 tumor suppressor protein, involved in sarcomas and other cancers.

Oncogenes drive abnormal cell proliferation as a consequence of genetic alterations that either increase gene expression or lead to uncontrolled activity of the oncogene-encoded protein. Important proto-oncogenes include Ras, bcr-abl, c-myc, Genetic changes in proto-oncogenes include point mutations, translocations and amplification.

Ras may undergo a point mutation. If the mutation is in the GTP binding site, hydrolysis of GTP will be impaired, therefore Ras remains constitutively active.

A translocation, the transfer of a piece of one chromosome to another nonhomologous chromosome, may have one of two effects: destruction of the gene if the breaks occurs within the gene, or altered expression by transferring the gene to a region controlled by another enhancer/promoter. Reciprocal translocation of the c-abl proto-oncogene from chromosome 9 to chromosome 22 occurs in the middle of the bcr gene. The resulting Philadelphia chromosome has the 5’ section of bcr fused with most of c-abl. Normally, c-abl is a nuclear tyrosine kinase, but bcr-abl is a cytoplasmic protein with increased tyrosine kinase activity due to deletion of a negative regulatory SH3 domain.

Amplification is an increased number of copies of a particular gene per cell. This may occur as multiple replication forks occur at the same time at a particular gene (i.e. the sequences just replicated are themselves replicated). These extra genes may “pop out” of the chromosome and exist as discrete DNA particles called double minutes. Although the double minutes can be transcribed, they can only be replicate if reincorporated into a chromosome. A gene that can undergo such amplification is c-myc, which dimerizes with max to act as a transcription factor for genes involved in cell proliferation.

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Tumor Suppressor Genes

Tumor suppressor genes are normal cellular genes that inhibit cell proliferation and tumor development. These genes are lost or inactivated in many tumors. Tumor suppressor genes may be genes for cytoplasmic or nuclear proteins.

Genes for cytoplasmic proteins include APC, DPC4 and NF-1. APC (adenomatous polyposis coli) binds the cell adhesin proteins a- and b-catenin, and is involved in colon and stomach cancers. DPC4 is a cell growth inhibitor normally acting in the TGFb signaling pathway that is deleted in pancreatic, colon, bladder and biliary cancers. NF-1 is a Ras-GTPase activating protein (Ras-GAP), involved in neurofibromas and chronic myelogenous leukemia.

Genes for nuclear proteins include transcription factors like WTI, BRCA1/2 and p53; transcription regulators like RD and VHL; and cell cycle regulators like MTS1. WTI (Wilm’s tumor) is a transcription factor involved in renal cell carcinoma. BRCA1/2 is a DNA repair factor involved in breast and ovarian cancer. P53 is a transcription factor that promotes growth arrest and/or apoptosis, and is involved in a range of cancers. RB (retinoblastoma) is a cell cycle regulator involved in retinoblastoma, lung, bladder, breast and pancreatic cancer. VHL is an RNA polymerase II regulator involved in von-Hippel-Lindau disease (renal cell). MTS1 codes for p16, a CDK inhibitor involved in melanoma, acute lymophoblastic leukemia and pancreatic cancer.

P53 is a transcription factor that induces expression of the cdk inhibitor p21, causing cell arrest at the G1 checkpoint. P53 is itself downregulated by MDM2, which complexes with p53 and targets it for degradation. However, if the DNA damage is higher than can be repaired by the cell, p53 can induce apoptosis. Mutations of p53 ussually occur at several “hot spots” in the area coding for the DNA binding domain. Since p53 acts on DNA as a tetramer, a mutation of its gene may be either dominant or recessive. Complete deletion of one or both alleles will be a recesive trait, leading to occasional tumors of many types. A nonsense or splice site mutation resulting in protein truncation will be a recesive trait. In such a case, the mutated proteins will be unable to form tetramers. If one of the alleles is normal, there will be some p53 activity, although reduced. A missense mutation of the DNA binding region will be a dominant trait because the mutant protein will bind to normal p53, preventing the formation of functional tetramers. In a similar manner, HPV infection (produces a protein, E6, that binds to p53 tetramers) and MDM2 amplification will prevent p53 tetramers from binding to DNA, thus they are dominant traits.

Li-Fraumeni syndrome (LFS) is a rare autosomal dominant syndrome in which patients are predisposed to cancer. LFS has been linked to germline mutations of the tumor suppressor gene for p53. Families with constitutional mutations in the hot spot region have a more aggressive cancer phenotype than families with other p53 mutations. Families with mutations in the hot spot region include those with younger probands at the time of cancer diagnosis.

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Cool Web Site: Animations of Microtubules During Mitosis

Other Mutations

Defects in DNA mismatch repair genes can increase the probability of tumor development by allowing the accumulation of mutations. An example of such a tumor is hereditary nonpolyposis colon cancer (HNPCC), were one of the members of the MutS DNA mismatch repair proteins is mutated.

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Cell Death

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