19.4 Proto-oncogenes and Tumor-Suppressor Genes Are

Altered in Cancer Cells

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Section 19.4

• Proto-oncogenes are genes whose products promote cell growth and division

• These genes encode – transcription factors that stimulate expression of other genes – signal transduction molecules that stimulate cell division – cell-cycle regulators that move through the cell cycle

• An oncogene is a proto-oncogene that is mutated or aberrantly expressed and contributes to the development of cancer – Only one allele of the proto-oncogene needs to be mutated or

misexpressed to contribute to cancer • Confers a dominant cancer phenotype

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• In cancer cells, one or more proto-oncogenes are altered in such a way that their activities cannot be controlled normally

Section 19.4 • The products of tumor-suppressor genes normally

regulate cell-cycle checkpoints and initiate the process of apoptosis

• When tumor-suppressor genes are mutated or inactivated, cells are unable to respond normally to cell-cycle checkpoints or are unable to undergo apoptosis if DNA damage is extensive – Leads to more mutations and development of cancer

• ras genes encode signal transduction molecules that are associated with the cell membrane and regulate cell growth and division

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Section 19.4

• Mutations that convert the ras proto-oncogene to an oncogene freeze the ras protein into its active conformation, constantly stimulating the cell to divide

• The p53 tumor-suppressor gene encodes a nuclear protein that acts as a transcription factor that represses or stimulates transcription of more than 50 different genes – p53 protein is continuously synthesized but rapidly degraded,

thus present at low levels – Increased levels result from increases in protein phosphorylation,

acetylation, and other posttranslational modifications

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Section 19.4

• p53 can arrest the cell cycle at several phases • Cells lacking p53 are unable to arrest at cell-cycle

checkpoints or enter apoptosis in response to DNA damage

• Loss or mutation of both alleles of the RB1 tumor-suppressor gene contributes to the development of many cancers due to unregulated progression through the cell cycle

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• In familial retinoblastoma, a mutated RB1 allele is inherited • Sporadic retinoblastoma requires two independent mutational events of

RB1 within the same cell

Section 19.4

• The retinoblastoma protein (pRB) is a tumor-suppressor protein that controls the G1/S cell-cycle checkpoint by preventing passage into S phase

• In many cancer cells, including retinoblastoma cells, both copies of the RB1 gene are defective, inactive, or absent, and progression into the cell cycle is not regulated

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19.5 Cancer Cells Metastasize and Invade Other Tissues

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Section 19.5

• To metastasize from the primary tumor, cancer cells must digest components of the extracellular matrix and basal lamina, which normally separate the body’s tissues and thus inhibit migration of cells

• Once cancer cells have disengaged, they enter the blood or lymphatic system and may become lodged in the microvessels of other tissues – Only about 0.01% of metastatic cells become metastatic tumors

• Metastasis is controlled by a large number of genes, including those that encode cell adhesion molecules, cytoskeleton regulators, and proteolytic enzymes 13

Section 19.5

• Proteolytic enzymes such as metalloproteinases are present at higher than normal levels in highly malignant tumors and are not susceptible to the normal controls conferred by regulatory molecules such as tissue inhibitors of metalloproteinases (TIMPs)

• Breast cancer cells that metastasize to bone express metalloproteinase gene MMP1

• Those that spread to the lungs express MMP1 and MMP2 genes

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Section 19.5

• The level of aggressiveness of a tumor correlates positively with the levels of proteolytic enzyme activity expressed by the tumor

• Like tumor-suppressor genes that are mutated in primary cancers, metastasis-suppressor genes are mutated or disrupted in metastatic tumors

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19.6 Predisposition to Some Cancers Can Be Inherited

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Most cancers result from somatic cell mutations but 50 forms of hereditary cancer (1–2%) are known

Section 19.6

• Most inherited cancer-susceptibility alleles are not sufficient in themselves to trigger cancer development

• At least one other somatic mutation in the other copy of the gene must occur to drive a cell toward tumorigenesis – Loss of heterozygosity

• Mutations in other genes are also usually necessary to

fully express the cancer phenotype. An example is the development of familial adenomatous polyposis (FAP)

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Section 19.6

• The APC (adenomatous polyposis) acts as a tumor suppressor controlling cell-cell contact and growth inhibition

• FAP results from one mutant copy of the APC gene (chromosome 5, deletions frameshift and point mutations) – Heterozygous APC mutation causes formation of hundreds to

thousands of rectal polyps or adenomas in early life – Second APC mutation leads to later stage of cancer

19.7 Viruses Contribute to Cancer in Both Humans and Animals

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Section 19.7

• Most animal viruses that cause cancer are retroviruses

• Viruses that cause cancer in animals are known as acute transforming retroviruses because they transform cells into cancer cells

• Retroviruses integrate into the host genome as a provirus that is replicated with the host’s DNA during the normal cell cycle

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Section 19.7

• A retrovirus can cause cancer by integrating near a proto-oncogene or by integrating a copy of a host proto-oncogene into its genome

• The RNA genome of the virus is copied into DNA by the reverse transcriptase, which is brought into the cell by the infecting virus. The DNA copy enters the host cell DNA and integrates at random

• The integrated DNA copy is called a provirus and gets replicated

along with the host DNA

• A retrovirus may not kill a cell but continue to use it as a factory to replicate more viruses that will then infect surrounding cells

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Section 19.7

• Retroviruses cause cancer in three ways – The proviral DNA may integrate by chance near one of the

normal proto-oncogenes and stimulate high levels of transcription of the proto-oncogenes

– Acute transforming retroviruses pick up a copy of a host proto-oncogene and integrate it into its genome. This may be mutated during viral transfer and transform normal cells into tumor cells

– A normal retrovirus with normal viral gene products can stimulate inappropriate cell growth

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Section 19.7

• No acute transforming retroviruses have been identified in humans, but there are several retroviruses associated with human cancers – Human immunodeficiency virus (HIV) – Human T-cell leukemia virus (HTLV-1)

• About 15% of human cancers are associated with viruses, making them the second-greatest risk factor, second to tobacco smoking

• The most significant contributors to virus-induced cancers are papillomaviruses (HPV 16 and 18), HTLV-1, hepatitis B virus, human herpesvirus 8, and Epstein Barr virus

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19.8 Environmental Agents Contribute to Human Cancers

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Section 19.8 • Any substance or event that damages DNA has the potential to be

carcinogenic if it causes mutations to occur in proto-oncogenes or tumor-suppressor genes

• Carcinogens, both natural and human-made, include chemicals, radiation, some viruses, and chronic infections

• The most significant environmental carcinogen is tobacco smoke, which contains at least 60 mutagenic chemicals, giving smokers a 20-fold increased risk of developing lung cancer

• Consumption of red meat and animal fat has been associated with colon, prostate, and breast cancer. Alcohol may cause inflammation and lead to liver cancer

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Section 19.8

• Some natural substances and natural processes are potentially carcinogenic

• Mold on bread and corn, aflatoxin, is one of the most carcinogenic chemicals known

• Naturally occurring nitrosamines, used as meat preservative, are known to cause cancer

• Naturally occurring and synthetic pesticides and antibiotics can be carcinogenic

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Section 19.8

• Both UV light and ionizing radiation (X rays and gamma rays) induce DNA damage

• UV sunlight can cause skin cancer

• Radon gas may be responsible for up to 50% of the ionizing radiation exposure to the U.S. population and contribute to lung cancer

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