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156 Cards in this Set

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What are the two basic components of tumors?
1. Transformed cells
2. The non-transformed supportive tissue (connective tissue and blood vessels)
Adenoma
Benign epithelial tumor of glandular origin or looks like glandular tissue
Papillomas
Epithelial tumor that grows finger-like projections
Polyp
Tumor that projects into the mucous of hollow viscus
Carcinomas
Malignant tumor arising from epithelial tissue
Sarcoma
Malignant tumor arising from mesenchym
How many germ layers is a mixed tumor derived from?
One germ layer
What type of cells are teratomas derived from?
Totipotent cells
How many layers are teratomas derived from?
Multiple germ layers - usually all three
Where are teratomas usually seen?
1. Testis
2. Ovary
What are two examples of non-neoplastic lesions that are mistaken for tumors?
1. Hamartoma
2. Choristoma
Hamartoma
Disorganized tissue indigenous to a particular site
Choristoma
Ectopic rests of nontransformed tissue
What are the four categories for the designation of malignant change
1. Differentiation
2. Growth rate
3. Invasion
4. Metastases
What is differentiation?
The extent of which transformed cells resemble normal cells.
Which type of tumor is usually more differentiated?
Benign tumors
What is a lack of differentiation called?
Anaplasia
What are the six histological characteristics that are used to characterize anaplasia?
1. Nuclear and cellular plieomorphism
2. Dark staining nuclei and prominent nucleoli
3. Nuclear to cytoplasm ratio
4. Apolarity
5. Abundant mitoses
6. Tumor giant cells
Well differentiated tumors tend to have what property?
They have whatever properties that the normal cells have.

i.e They could produce hormomes or keratin
What is dysplasia?
Unorganized, non-neoplastic growth
When do you consider dysplasisa to be a carcinoma in situ?
When the disorganized growth of cells spans the entire thickness of the epithelium but does not break the basement membrane.
What is the forerunner of invasive carcinoma?
Carcinoma in situ
What type of tumor typically grows the fastest?
Malignant
How could pregnancy or menopause affect the growth of a tumor?
If the tumor was hormone sensitive, it would respond to the varying levels of hormones associated with pregnancy or menopause.
Fast growing tumors have a high ________.
Cell turnover rate
What does it mean to have a high cell turnover rate?
It means that the cells in the tumor are going through both replication and apoptosis very quickly.
What is the growth fraction and why is it important?
1. The growth fraction is the percentage of cells in a tumor that are replicating.
2. The size of the growth fraction is important because most of our anti-tumor drugs target cells that are dividing.
What does growth rate strongly correlate with?
Level of differentiation - the more differentiated the slower it grows.
How many cells does a clinically detectable tumor usually have?
10^9 cells
What type of cells ulimately initiate and sustain tumor growth? Why would finding these be important?
1. Tumor stem cells
2. If you could wipe these out, the source of the tumor would be wiped out as well.
Why don't benign tumors typically invade local tissue?
They growth with a compressed ring of connective tissue around the tumor that prevents invasion.
Are malignant tumors typically invasive?
Yes, very invasive. This makes surgical ressection very difficult.
What is the single most important feature the distinguishes malignant tumors from benign ones?
Malignant tumors have the capability to metastasize.
What are the three ways tumors metastasize?
1. Seeding of body cavities
2. Invasion of lymphatics
3. Hematogenous spread
What type of cancers typically spread hematogenously?
Sarcomas
What type of carcinomas typically spread hematogenously?
Renal cell carcinomas
What type of blood vessels are more typically involved and why?
Veins because they are thinner and therefore easier to invade.
What two sites are most typically invaded after cancer invades veins?
1. Liver
2. Lungs
Cancer is more common once you hit what age?
55
Cancer is the most common cause of death in what age population in men and women?
1. Men: 60-79
2. Women: 40-79
What are the five most common cancers in children younger than 15 years of age?
1. Tumors of the hematopoietic system
2. Neuroblastomas
3. Retinoblastomas
4. Wilms tumors
5. Sarcomas of the bone and skeletal muscle
Less than ___% of people with cancer have an inheritable type?
10
Genetic predispositions to cancer can be broken down into what three categories?
1. Autosomal dominant inherited cancer syndromes
2. Defective DNA repair
3. Familial carriers
Autosomal dominant cancers typically involve what type of mutation?
Point mutation to a tumor supressor gene that disables one allele. They other allele is disabled somatically in life.
What are three common characteristics of autosomal dominant cancers?
1. Relegated to a particular tissue (not an increased risk to all cancers)
2. Tumors usually have a marker phenotype
3. Incomplete penetrance and variable expressivity
Heriditary nonpolyposis colon cancer is due to what type of mutation?
Heriditary defective DNA mismatch repair mechanism
What are three common characteristics of familial cancers?
1. Development of tumors (usually multiple or bilateral) at an early age
2. No marker phenotype
3. Usually inherited via autosomal dominant fashion but multifactorial, enviromental and incomplete penetrance/variable expressivity cannot be ruled out.
What are two nonheriditary predispoing conditions that can lead to cancer development?
1. Chronic inflammation
2. Precancerous conditions
Why would chronic inflammation lead to cancer (4)?
1. Constant stimulation and release of cytokines that stimulate the growth of transformed cells
2. Cytokines induce genomic instability
3. Cytokines increase the pool of cells that would be subject to the effect of mutagens
4. ROIs can indirectly damage DNA
What lies that the heart of carcinogenesis?
Non-lethal genetic damage
How can monoclonality of tumors be verified?
X-linked markers
What are the four classes of regulatory genes that are targets of genetic damage?
1. Proto-onco genes
2. Tumor suppressor genes
3. Genes that regulate apoptosis
4. Genes that regulate DNA repair
What does tumor progression refer to?
Stepwise aquistition of mutations allowing the progression of a cell line towards cancer.
What cylin/CDK combo allows the releasal of E2F from Rb?
CyclinD/CDK4 hyperphosphorylates Rb causing it to dissociate from E2F allowing DNA replication to take place.
Which cylin/CDK combos are responsible for entry into M phase of the cell cylce?
1. CyclinB/CDK1
2. CyclinA/CDK2
What are the two main classes of CDK inhibitors?
1. Cip/Kip (p21, p27, p57)
2. INK4/ARF (p16INK4a and p14ARF)
Transcriptional activation of p21 is controlled by what?
p53
Cell cyle arrest at the G1/S checkpoint is mainly mediated by what?
p53
Cell cyle arrest at the G2/M checkpoint is mainly mediated by what?
Both p53 dependent and p53 independent mechanisms
p27 responds to what signal?
TGF-B
How does p16INK4a inhibit the cell cycle?
It binds to cylinD-CDK4 and promotes the inhibitory affects of Rb.
How does p14ARF inhibit the cell cycle?
It increases p53 levels by inhibiting MDM2.
How does p53 mainly act in the G1/S checkpoint? What regulates levels of p53?
1. Mainly acts through p21
2. Causes the transcription of proapoptotic genes such as BAX and BID
3. MDM2
How is ATM activated?
It is activated through mechanisms that sense double-stranded breaks in DNA.
How does ATM influence the G1/S checkpoint?
Mainly through the actions of p53.
How does ATM influence the G2/M checkpoint?
1. p53 dependent mechanisms
2. CDC25 phosphotase - disrupts the cyclin B-CDK1 complex
ATM is a component of what network of genes? What do they do?
1. BRCA1 and BRCA2
2. Link DNA damage with cell-cycle arrest and apoptosis
Proto-oncogenes can be converted to oncogenes through what three mechanisms?
1. Point mutations
2. Translocations or inversions
3. Gene amplification
Are most human tumors v-onc or c-onc and how would you test to distinguish the two?
1. c-onc
2. Transfect the tumor derived DNA into mouse fibroblast cells and observe their behavoir.
What are three classes of proto-oncogene products that could lead to the development of cancer?
1. Affected growth factor products
2. Affected growth receptors
3. Affected signal transduction genes
What percentage of human tumors carry mutatant RAS proteins?
15% to 20%
What pathway does the RAS system turn on?
MAP kinase which results in cellular proliferation.
What type of mutation is frequently seen in RAS mutations? What is the result?
Point mutations that inhibit intrinsic GTPase activity rendering the molecule constantly "ON".
An alteration of c-ABL gene results in what?
Unregulated tyrosine kinase activity (usually only activated when mitogenesis is needed)
What disease is caused by consitutent activation of c-ABL (BRC-ABL transloaction 9:22 aka Philidelphia chromosome)?
Chronic myeloid leukemia
What type of molceule is the c-ABL gene product?
Non-receptor tyrosine kinase
Dysregulation of MYC results in what(3)?
1. Burkitt lymphoma
2. Neuroblastoma
3. Small cell cancer of the lung
MYC gene product has what type of function?
Transcription factor
What syndrome is associated with inherited loss of one allele of p53?
Li-Fraumeni syndrome
What is APC's function?
It regulates levels of B-catenin which is an up-regulator is c-MYC, cyclin D1 and other genes.
What is the result of the inactivation of APC?
The formation of thousands of andeomatous polyps in the colon. One or more will likely become malignant.
What percentage of sporadic colon cancers have homozygous loss of APC alleles?
70% to 80%
What kind of function does TGF-B have in the regulation of the cell cycle?
TGF-B binds to TGFRs and upregulate the transcription of gene products the inhibit cellular growth.
Which type of TGF-B receptor is muatated and no longer signals for the upregulation of inhibitory factors? What type of cancer is this seen in? What percentage have this mutation?
1. Type II TGF-B receptors
2. HNPCC
3. 70%
Where else can you see mutations in the TGF-B pathway that could result in cellular proliferation? What type of cancers are these seen in?
1. SMAD2 and SMAD4
2. Pancreatic and colorectal tumors
The NF-1 gene regulates signal transduction in what system?
RAS
What is the result of homozygous inactivation of the NF-1 gene?
RAS is locked into the active GTP bound state (loss of GTPase activity).
What type of tumors do you develop with inactivation of the WT-1 gene?
Wilms tumors
What is the WT-1 gene normally involved in?
Renal and gondal differentiation
What cancer do you see the most dramatic over-expression of BCL-2? What do you see in 85% of these tumors?
1. Follicular B-cell lymphomas
2. (14:18) Translocation of the BCL-2 gene to a transcriptionally active heavy chain immunoglobin
What role does p53 play in relation to apoptosis?
It regulates the expression of BAX (pro-apoptotic gene).
Cells that have mutations in their DNA repair mechanisms are said to be ________.
Genomically unstable
Are DNA repair genes directly oncogenic?
No
What are the three DNA repair systems that mutations can affect?
1. Mismatch repair
2. Nucleotide Excision Repair
3. Recombination repair
What type of cancer is seen with a defect in mismatch repair?
Carcinomas of the rectum or proximal colon that do not have an adenomatous polyp preneoplastic phase.
What are the two DNA mismatch repair genes?
1. MSH2
2. MLH1
How can errors in DNA mismatch be readily documented and examined?
Examine microsatellite repeats
What is a hallmark of mismatch repair defects?
Microsatellite instability
Xeroderma pigmentosum is associated with what DNA repair disorder?
Nucelotide excisional repair
What are three examples of diseases that are the result of defective recombination repair?
1. Bloom syndrome
2. Fanconi anemia
3. Ataxia-telangiectasia
What is the defect in Ataxia-telangiectasia?
Defect in ATM prevents it from being able to recognize breaks in double stranded DNA. This means that it will not phosphorylate p53, allowing cell cycle progression.
BRCA-1 and BRCA-2 are both involved in what process?
repair of double-stranded DNA breaks by homologous recombination.
What enzyme is active in somatic tumor cells that is not normally active?
Telomerase
What do tumors need to be able to grow to sizes larger than 1mm to 2mm in diameter?
Blood supply
When new vessel in-growth occurs, what happens that can cause tumor proliferation?
The release of proliferation factors such as PDGF and insulin-like growth factor.
What factors derived from tumors cause angiogenesis?
1. bFGF
2. VEGF
How is tumor vasculature different from normal vasculature?
Tumor vasculature tends to be more tortuous, irregular and leaky.
When the switch to angiogenic phenotype in tumors is made, you see the loss of what?
Angiogenesis inhibitors such as thrombospondin-1 (produced by p53).
What anti-angiogenic factors will a tumor also release?
Angiostatin and endostatin
What is the first thing that must happen in order for a tumor to metastasize?
The cells must detch from the tumor by loosening the binding of E-cadherins.
What step is after the detachment of the tumor cells?
The adhesion to the ECM by way of surface receptors.
What step is after adhesion to the ECM?
Degradation of the ECM by enzymes.
What can be correlated to metastatic potential?
The ability to degrade the ECM.
What enzymes are used to degrade the ECM? What do these enzymes act on?
1. Type IV collagenases
2. Cathespin D (cyestine protease)
3. Urokinase plasminogen activator
4. Laminin, fibronectin and proteoglycan cores
What is a special trick that tumor cells migrating the blood supply use to avoid death by circulating T cells?
They form emboli by adhering to platelets.
What are three factors in the where the emboli lodge?
1. Vascular and lymphatic drainage
2. Interaction of tumor cells with tissue specific receptors
3. The microenviroment (antiprotease levels)
High levels of the CD44 adehsion molecule would allow diapediesis in what tissues?
High endothelial veins that allow them to get into lymph nodes
There is over expression of what gene in 25% of neuroblastomas? In 20% of breast cancers?
1. N-myc
2. ERB-B2
Is a single mutation sufficient to cause the transformation into a malignant cell line?
No, it is a multistep process that involves many mutations to get to a malignant state.
By the time tumors are clinical evident, are the said to be _________.
Very heterogeneous even though the are monoclonal in origin.
What are three classes of agents that cause genetic damamge and induce neoplastic transformation?
1. Chemical carcinogens
2. Radiant energy
3. Oncogenic viruses and other microbes
What is involved in induction?
Induction is the induction of certain irreversible changes (mutations) in the genomes of cells.
Are initiated cells transformed?
No they do not exhibit autonmous growth or unique phenotypic characteristics.
When do initiated cells give rise to tumors?
When they are appropriately stimulated by promoting agents.
Do promoters affect DNA themselves? Are the mutagenic?
No and no. All they do is amplify cellular proliferation of initiated cells thereby increasing the chance that transformation will take place.
Most carcinogens are in what form?
They are in a procarcinogenic form that requires activation by metabolism - usually by the p450 oxygenase system.
What is common among all direct-acting and procarcinogenic agents?
Extreme nucleophiles
What is the name of the test that can test the carcinogenic capabilities of a compound?
Ames test - carcinogen is applied to the bacterium Salmonella typhimurium.
What are the most commonly used promoters used in experimental settings?
Phorbol esters - non-mutagenic
What is tetradecanoyl phorbol's MOA?
It activates Protein kinase C and causes activation of its cascade leading cell proliferation and differentiation.
What are two examples of direct acting alkylating agents?
1. Cyclophosphamide
2. Busulfan
3. Immunosupressants
What type of carcinogen is typically seen in cigarette smoke?
Polycyclic aromatic hydrocarbon
B-Napthylamine causes high incidences of what type of cancer?
Bladder cancer
What is believed to be the cause for the high incidence of liver cancer in Africa?
Aflatoxin B1 from the fungus Aspergillus flavus.
Nitrosamines and amides cause increased rates of what type of cancer?
Gastric cancer
What type of UV causes the greatest incidence of cancer?
UVB
What are the two mechanisms of which UV light can cause cancer?
1. Thymine dimers
2. Immunosuppression
What are the proposed mechanisms of which electromagnetic or particulate radiation cause mutations?
1. Direct affect of radiant energy
2. Formation of free radicals from water or oxygen
What type of ionizing radiation is more carcinogenic?
Particulate radiation
Therapuetuic radiatation to the neck in children cause high incidence of what type of cancer?
Thyroid cancer
What is the order of incidence of cancer due to ionizing radiation?
1. Meyloid leukemias
2. Thyroid cancer in children
3. Breast and lung
4. Skin, bone and gut
What are four different viruses known to be implicated in human cancer?
1. Human papillomavirus (HPV)
2. Epstein-Barr virus (EBV)
3. Hepatitis B virus (HBV)
4. Kaposi sarcoma herpesvirus (KSHV)
Which HPV types are seen in squamous cell cancers of the uterine cervix?
Types 16 or 18
Which HPV types are seen in genital warts?
Low risk types ie HPV 6 or 11
Viral integration causes increased levels of what viral proteins are seen in cervical cancer?
E6 and E7 which inhibit p53 and Rb
EBV causes what problem primarily?
Burkitt lymphoma (t8:14) activates the MYC gene.
EBV causes what cancers?
1. Burkitt lymphoma
2. Nasopharyngeal carcinoma
3. B Cell lymphomas in immunodeficient patients
4. Hodgkin lymphomas
Hepatitis B is associated with what type of cancer? What is the leading theory on why?
1. Liver cancer
2. Due to the damage caused by the virus, cellular proliferation picks up which causes an increase in the probablity that mutations occur.
What transcriptional activator is associated with viral hepatitis B? What else might it do?
1. HBx - upregulates proto-onco genes
2. Bind p53
What is the only retrovirus that has been implicated in causing cancer?
HTLV-1
What type of cells is HTLV-1 trophic for?
CD4 T cells
Does HLTV-1 contain an oncogene?
No
HLTV-1 encodes for the production of what factor? What does it do?
1. TAX
2. Upregulates IL-2 production which activates more T cells
What is the cancer that results from the bacterium Heliobacter pylori? What is special about the B cells in this cancer?
1. Mariginal Zone Lymphoma - MALToma
2. They are T cell independent
The levels of what compound are useful in estimating tumor burned or recurrences in what type of cancer?
1. Carcinoembryonic antigen (CEA)
2. Colon cancer
Elevated levels of what protein are seen in liver and testicular cancer?
Alpha-fetoprotein