Cell Biology: Cancer

immune system and cancer

-mutant mice, which have no immune response because of mutations in the Rag2 gene, exhibit increased rates of cancer -AIDs patients have increased rates of only certain type of cancers, which suggests that the immune system may defend us mainly from virus-induced cancers -cancers can evade destruction by the immune system -different cells of a tumor may express different antigens -as tumors grow, there is selection for cells that elicit a weaker immune response -cancers can also confront and overcome the immune system -come cancers produce molecules that kill or inhibit the function of T lymphocytes, or surround themselves with dense tissue that shields them from immune attack -some divide so quickly that the immune system cannot kill them fast enough to check tumor growth

src

-mutant viruses with defects in src can infect cells and reproduce normally but cannot trigger cancer -thus, a functional copy of src much be present for cancer to arise

cell differentiation in skin

-new cells continually replace aging cells shed from the outer body surface -new cells are generated by cell divisions in the basal layer of the skin

anchorage-independent growth

-normal cells do not grow well in culture unless provided with a solid surface they can attach to -in contrast, cancer cells grow well not only when anchored to a solid surface abut also when suspended in liquid or semisolid medium

Cancer Cells vs telomere length

-normal cells grown in culture divide a limited number of times -under similar conditions, cancer cells exhibit no such limit and continue dividing indefinitely

density-dependent inhibition of growth

-normal cells grown in culture divide until the surface of the vessel is covered by a single layer of cells -once this monolayer is reached, cell division stops

cancer cells vs. restriction point

-normal cells grown under suboptimal conditions become arrested at the restriction point and stop dividing -the restriction point controls progression from G1--> S -cancer cells are unresponsive to external signals and to internal conditions that would normally trigger a halt to the cell cycle

proto-oncogenes

-normal cellular genes from which oncogenes arise after mutation -these are normal genes that contribute to regulation of cell growth and survival -if and when the structure of this gene is altered, the mutated form can cause caner

two main classes of affected genes

-oncogenes -tumor suppressor genes

When a basal cell divides, it gives rise to two cells...

-one stays in the basal later and can still divide -one differentiates and moves toward the skin surface

Oncogenes

-one whose presence can trigger the development of cancer -some introduced to the cell by cancer-causing viruses -others arise from mutation of normal cellular genes -RAS was just the first of over 200 human oncogenes identified -a single oncogene is not sufficient to cause cancer -MULTIPLE MUTATIONS ARE USUALLY REQUIRED TO CONVERT A NOMRAL CELL INTO A CANCER CELL

3.) chromosomal translocation

-part of one chromosome is physically removed and joined to another chromosome -the Burkitt lymphoma, frequently, a proto-oncogene called MYC is moved form chromosome 8 -it becomes situated next to a highly active region of chromosome 14, causing MYC to be highly transcribed

Immune Surveillance Theory

-postulates that immune destruction of cancer cells is common -cancer is an occasional failure of immune response -transplant patients who take immunosuppressive drugs develop cancers at higher rates than normal

cell differentiation

-process by which cells acquire specialized properties -as cells acquire these specialized traits, they lose the capacity to divide

4.) Nonreceptor Protein Kinases

-protein phosphorylation reactions are often used to transmit signals within the cell via nonreceptor protein kinases -several oncogenes encode proteins involved in the cascade of phosphorylation reactions that follow Ras activation

5.) insertional mutagenesis

-retroviruses can sometimes cause cancer even if they have no oncogene of their own -they do this by integrating their genes near a proto-oncogene on the host chromosome, leading to over expression of the gene -this insertional mutagenesis is frequent in animal cancers but rare in humans

5. Transcription Factors

-some growth-signaling pathways trigger changes in transcription facotrs, thus altering gene expression -a common oncogene encodes the Myc transcription factor -Burkitt lumphoma is one of several human cancers in which the Myc protein is overproduced

oncogenes with other functions

-some oncogenes inhibit apoptosis rather than stimulating cell division -the protein Bcl-2 inhibits apoptosis: translocations involving this gene are seen in some lymphomas -the MDM2 gene can cause a failure of apoptosis when the gene is amplified or abnormally expresesd

other oncogenic receptors

-some oncogenes produce normal receptors but in excess quantities, such as ERBB2 -some signaling pathways use receptors that stimulate activity of independent tryosine kinases -an oncogene, v-mpl, from myeloproliferative leukemia virus, encodes a mutant form of thrombopoietin that uses the Jak_STAT pathway to stimulate proliferation of platelets

transit-amplifying cells

-stems cells can sometimes produce daughter cells that are more specialized and continue to divide

precarcinogens

-substances that much be activated before causing cancer -most are activated in the liver by members of the cytochrome P450 enzyme family -these catalyze the oxidation of foreign chemicals to make them less toxic and easier to eliminate from the body

Judah Folkman

-suggested that tumors release signaling molecules that trigger angiogenesis, and the new blood vessels are needed for tumors to grow

Telomeres

-telomere DNA sequences are lost from the ends of each chromosome whenever DNA replicates -if a cell divides too many times, the telomeres are too short to protect the ends of chromosomes -apoptosis is triggered

RB

-the Rb gene product is required to prevent cells from passing through the G1 restriction point without an appropriate signal from a growth factor -mutations in the gene disrupt the normal controls on cell proliferation: this effect is also seen in other types of cancers -mutations in RB are detected in nonhereditary retinoblastomas and other nonhereditary cancers

Angiogenesis

-the action of MMPs allows endothelia cells to migrate into the surrounding tissues -they become organized into hollow tubes and develop into new blood vessels -VEGF and FGF must overcome angiogenesis inhibitors in order to promote blood vessel formation

examples of human cancers that involve cell cycle and apoptosis regulators

-the cdk gene CDK4 is amplified in some sarcomas -Cyclin, CYCD1, is commonly amplified in breast cancers -it is altered by translocation in some lymphomas

teromerase

-the enzyme that adds telomere sequences to the ends of DNA molecules -produced by most cancers

How Cancers Spread

-the hazards of cancer come from uncontrolled proliferation combined with the ability to spread throughout the body -roughly 90% of cancer deaths are caused by the spread of the cancer rather than the primary tumor

chemicals causing cancers

-the list of known and suspected carcinogens has grown to include hundred of different chemicals -many carcinogens share a need for metabolic activation before they can cause caner -in the liver, 2-naphthylamine is metabolized into other chemicals that actually cause cancer

tumor suppression and oncogenes

-the the hybrid cells, tumor suppression is observed even when the original cells possessed an oncogene such as RAS -the ability to form tumors does not appear until the hybrid cell loses a chromosome containing a critical tumor-suppressor gene -tumor suppressor genes can be identified in families with heritable forms of cancer: they have increased susceptibility to cancer

blood flow and organ-specific factors determine sites of metastatsis

-though the bloodstream carries cancer throughout the body, metastases develop preferentially at certain sites -cancer cells are most likely to become lodged in capillaries -for tumors of most organs, the first capillary bed the cancer will encounter is in the lungs, but for others it is in the liver

Tumor Microenvironment

-tumor cells interact with the surrounding tumor microenvironment, which includes normal cells, extracellular molecules, and components of the EMC the microenvironment may facilitate or inhibit the ability of tumor cells to metastasize

Experimental Evidence of Angiogenesis

-tumor cells transplanted to the anterior chamber of the eye of a rabbit form tiny tumors that soon stop growing -when the cells are transplanted to the iris area, which has a blood supply, the tumors are infiltrated by blood vessels -the tumors grow to thousands of times the original size

clonal expansion

-tumor progression -selection will favor cells that exhibit enhanced growth rate and invasive properties -these form a large population through clonal expansion

the Philadelphia chromosome

-version of chromosome 22 that has undergone a translocation with chromosome 9 -the translocation creates an oncogene called BCR-ABL, which produces a fusion protein of the BCR and ABL genes -it is commonly associated with chromic myelogenous leukemia

ionizing radiation

-x-ray and related types of radiation because they remove electrons from molecules -x-rays create DNA mutations and cause cancer in direct proportion to the dose administered -a luminescent paint containing radium, used for painting watch dials, was found to trigger cancer int he workers who used the paint

oncogenes from cancers not caused by viruses

-DNA from isolated human bladder cells was introduced to cultured mouse cells (3T3 cells) -DNA is administered by a method that stimulates transfection, the uptake of foreign DNA into cells and its incorporation into their chromosomes -A mutant form of the human gene called RAS was associated with the ability of the cells to promote cancer

how aberrant traits arise

-TUMOR PROGRESSION (continued) -not clear how aberrant traits arise in the first place -one way is through additional DNA mutations that occur after the original, initiating mutation -new traits may also arise by changes in expression of normal genes -numerous epigenetic mechanisms -not all cells in a tumor are equally capable of rapid proliferation -tumors may contain small groups of cells that act like cancer stem cells to generate large numbers of descendants

stem cells

-a stem cell can divide to form more cells like itself or cells that are destined to become more specialized

promotion

-a year or more may elapse after feeding animals a dose of DMBA, and tumors can still develop if the skin is irritated with croton oil -this means that DMBA creates a permanently altered initiated state in cells throughout the body -Initiators cause DNA damage; the initiated state is based on the initiation of DNA mutations -promotion is a gradual process requiring prolonged or repeated exposure to a promoting agent -the main shared feature of promoting agents is the ability to stimulate cell proliferation -not all tumor promoters are foreign substances: hormones and growth factors may inadvertently behave as tumor promoters

Loss of Heterozygosity

-an inactivating mutation in the second copy of a tumor suppressor gene can lead to cancer -When all or part of a chromosome containing the normal allele of the gene is deleted, this is called loss of heterozygosity (LOH) -LOH can be confirmed by looking for deletion of microsatellite or shot tandem repeat (STR) markers on the chromosome

"Seed and Soil" hypothesis

-blood-flow pattern alone does not explain the location of metastases -Paget proposed the "seed and soil" hypothesis -it says that cancer cells are carried around the body, but only a few sites provide an optimal growth environment for each type of cancer

proteases

-cancer cells also produce proteases that degrade protein-containing structures -such structures would act as barriers to cancer cell movement

tumor progression

-cancer cells have lost normal controls of cell proliferation -one idea of how progression occurs is that cells are like organisms under natural selection

process of degradation of basal lamina

-cancer cells secrete proteases that degrade proteins in the basal lamina 1.) the protease plasminogen activator converts inactive plasminogen into the active plasmin 2.) plasminogen degrades components of the basal lamina and the ECM -it also cleaves inactive precursors of the matrix metalloproteinases that are then also able to degrade the basal lamina and ECM

cancer cells vs. density-dependent inhibition of growth

-cancer cells will continue to divide and pile up upon one another, lacking sensitivity to density-dependent inhibition

Cancer arising

-cancer development requires multiple steps -normal cells are converted into a precancerous state and sensitized to further change in a process called initiation -during the long, gradual process of promotion, sensitized cells are repeatedly exposed to cancer-promoting agents -once a tumor has formed, the tumor grows and differentiates in the process of tumor progression

What causes cancer?

-cancers are commonly caused by environmental agents and lifestyle factors -most of these act by triggering DNA mutations -epidemiological data have allowed many causes of cancer to by identified

Metastasis-process

-cascade of events is required for a tumor to metastasize, beginning with angiogenesis -first, cancer cells invade surrounding tissues and gain access to the bloodstream -second, they are transported throughout the body -third, they leave the bloodstream and establish new metastatic tumors in various organs

UV radiation

-causes cancer by damaging DNA -is absorbed mainly by the skin, where it triggers pyrimidine dimer formation: formation of covalent bonds between adjacent pyrimidine bases in DNA -if this damage is not repaired, it can cause incorrect nucleotides to be incorporated during replication of DNA

Changes in Cell Adhension

-cell-cell adhesion proteins that cause cells to adhere to one another are often missing or defective in cancer cells -one crucial molecule is E-cadherin

1. Growth Factors

-cells do not normally divide unless stimulated by an appropriate growth factor -cells infected with the simian sarcoma virus produce a mutant form of PDGF, which continually stimulates the cells' proliferation -some human sarcomas contain a PDGF-related oncogene

Defects in Signaling Pathways, Cell Cycle Controls, and Apoptosis Contribute to Cancer

-cells do not usually divide unless stimulated by the proper growth factor cancer cells circumvent this by altering signaling pathways, creating a constant signal to divide -disruption of cell cycle control also contributes to cancer cell proliferation

cancer crucial issue

-crucial issue is not rate of division but the balance between division and differentiation or cell death

RB tumor suppressor Gene

-discovered by studying families with hereditary retinoblastoma -children with rentinoblastoma inherit a deletion of part of chromsome 13 -individual retinal cells may occasionally acquire a deletion or mutation in the same region of chromosome 13 -cancers arise from such cells -the RB gene was identified as responsible for this

epidemiological data

-epidemiological data have been important in helping identify lifestyle and environmental causes of cancer -an example is the connection between cancer and cigarette smoking -smoking is linked to lung cancer, as we as cancers of the esophagus, stomach, pancreas, uterine cervix, kidney, bladder, and colon

Initiation

-evidence for initiation and promotion came from studying ability of DMBA to cause cancer in lab animals -a single dose of DMBA rarely causes tumors to develop in mice -if a moues fed a single dose is later treater with a substance that causes skin irritation, a cancer develops in the treated area -the most commonly used irritant for triggering tumors is croton oil -this plant derivative is rich in compounds called phorbol esters -croton oil doesn't cause cancer by itself, nor does cancer arise if the DMBA is administered after the croton oil

blood vessel growth controlled by balance between angiogenesis activators and inhibitors

-experimental evidence suggests that cancer cells produce molecules that activate angiogenesis in the surrounding tissues -the main angiogenesis-activating molecules are (VEGF) and (FGF) -when cancer cells release VEGF and FGF into the surrounding tissue, they bind to receptors on endothelial cells lining blood vessels -the binding activates a signaling pathway: in response, the endothelial cells divide and secrete MMPs -the MMps break down the ECM

oncogenes from viruses

-first oncogene discovered was in the Rous sarcoma virus

cancer cells vs. apoptosis

-for some cancers, uncontrolled growth is due to a failure to undergo apoptosis, rather than to increased cell division -cancer cells are able to block the pathways that trigger apoptosis in various ways

polycyclic aromatic hydrocarbons

-found in cigarette smoke preferentially bind to regions of the p53 gene -mutations in the p53 gene play a role in many kinds of cancer

Burkitt lymphoma

-identified in 50s, shown to be associated with EBV

Voyage Through the Blood Stream

-if cancer cells penetrate the walls of blood vessels, they are transported around the body -cancer cells that enter the lymphatic system may become lodged in lymph nodes but can also eventually enter the blood stream -the bloodstream is a relatively inhospitable place for most cancer cells -relatively few cancer cells survive the voyage through the bloodstream

4.) local DNA rearrangements

-in local rearrangements, proto-oncogenes are altered by deletions, insertions, inversions, or transposition -a simple inversion involving the NTRK1 and TPM3 genes results in a fusion gene called the TRK oncogene -this fusion protein forms a permanent dimer, and the kinase is constantly activated

3.) plasma Membrane GTp-binding proteins

-in many growth0signaling pathways, growth factor binding of a receptor leads to Ras activation -oncogenes encoding mutant Ras proteins are a common genetic abnormality in human cancers -these hyperactive Ras proteins retain bound GTP instaed of hydrolyzing it to GDP

balance between division and differentiation

-in normal skin, one of the two cells produced by each division retains the ability to divide -the other cell leaves the basal layer, loses the ability to divide, and finally dies -this ensures no increase in number of dividing cells -cell division is carefully balanced with cell differentiation and death

integrins

-in the body, normal cells meet the anchorage requirement by binding to the ECM via integrins -attachment to the matrix can be prevented by blocking the binding of integrins to the matrix -in this case, normal cells lose the ability to divide and often self-destruct by apoptosis: cancer cells circumvent this safeguard

6. cell cycle and apoptosis regulators

-in the final step of growth-signaling pathways, transcription factors activate genes with products that control proliferation and survival -the activated genes include those the encode cyclins and Cdks -several human oncogenes encode proteins of this type

disruption of balance

-in tumors, cell division is uncoupled from cell differentiation and death -some cell divisions give rise to two cells that can both continue to divide -regardless of how fast or slowly the cells divide, the tumor will continue to grow as new cells are produced in greater numbers than needed

2.) gene amplification

-increase the number of copies of a proto-oncogene -about 25% of human breat and ovarian cancers have amplified copies of ERBB@ gene -the extra copies of this growth factor receptor cause excessive cell proflieration

The Two-Hit Hypothesis

-increased cancer susceptibility is usually an inherited defect in a tumor suppressor gene -two successive mutations int he same gene would be required to produce a loss of function in a tumor suppressor gene -If people inherit a mutation in one copy of the gene, there is a greater chance of sustaining a second mutation in the gene: Two-Hit Hypothesis

Cancer Cell Motility

-increased motility of cancer cells -it is stimulated by signaling molecules from the surrounding tissues or from the cancer cells themselves -some of these act as chemoattractants -activation of Rho Family GTP also plays a role

Why Do cancer cells Grow Best at Particular Sites?

-interactions between cancer cells and the microenvironment of the new location may be important -for instance, prostate cancer cells can be mixed with bone, lung, and kidney cells and then injected into animals -Those mixed with bone are more likely to form tumors because of growth factors produced by bone cells

1.) point mutation

-is a single nucleotide substitution that causes a single amino acid change in the protein produce of the gene -the most frequently encountered oncogenes of this type are RAS oncogenes -the mutations cause the Ras pathway to be continually activated, leading to excessive cell proliferation

tumor-suppressor genes

-loss or inactivation of T-S genes can lead to cancer -the normal function of such gees is to restrain cell proliferation -few dozen genes in human cells exhibit the properties of tumor suppressors

angiogenesis inhibitors

-many naturally occurring inhibitors known -include: angiostatin, endostatin, and thrombospondin -when tumors trigger angiogenesis, it is accomplished by increasing angiogenesis activators and decreasing angiogenesis inhibitors

2.) receptors

-many receptors exhibit tyrosine kinase activity that is activated when a growth factor binds the receptor -oncogenes sometimes encode mutant forms of the receptors that are permanently activated -the v-erb-b oncogene produces an altered form of the epidermal growth factor receptor that is constitutively active

oncogenes fall into six categories

1. growth factors 2. receptors 3. plasma membrane GTp-binding proteins 4. nonreceptor protein kinases 5. transcription factors 6. cell cycle or apoptosis regulators

invasion

direct migration and penetration of cancer into neighboring tissues

DNA mutations involved in cancer

generally affect genes that contorl cell proliferation and survival

benign tumors

grow in a confined local area and are rarely dangerous

epidemiology

branch of science that investigates the frequency and distribution of diseases in human populations -cancers arise with different frequencies in different parts of the world

epigentic mechanisms

can alter gene activity without mutating them

malignant tumors

capable of invading surrounding tissues and spreading to distant parts of the body

HTLV-1

causes adult T-cell lymphoma

H. pylori

common cause of stomach ulcers-- linked to stomach cancer

basal lamina

critical barrier encountered by most cancers

metastasis-definition

involves the ability of cancer cells to enter the blood stream and travel to distant sites

flatworm infections

linked to small number of bladder and bile duct cancers

Hepatitis B/C

liver cancers

intratumor heterogenetity

mixture of genetically distinct regions in a single tumor

carcinogenic activation

oxidation of precarcinogens inadvertently converts them into carcinogens

term "cancer"

refers to any malignancy; in particular, malignant cells that can spread to new locations

tumor

resulting mass of tissue -neoplasm

antigens

substances that trigger immune response

metastases

tumors formed in new locations

Cancer

type of growth in which some cells divide and accumulate in an uncontrolled way

HPV

uterine cerical cancer

DNA damage

-Carcinogens modify DNA in several ways 1.) generating crosslinks between two strands of the double helix 2.) creating chemical links between adjacent bases 3.) hydroxylating or removing individual bases 4.) causing breaks in one or both strands

Viruses in Development of Cancer

-Rous performed experiment on chickens that had cancers in connect tissues (sarcomas) -He showed that cancer can be caused by virus) -This was the first time anyone had detected an oncogenic virus (cancer causing) -it now known that dozens of viruses can cause cancer in animals -few linked to human cancers