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Block 7 week 1 > Cancer part 1 & 2 - Barsky > Flashcards

Cancer part 1 & 2 - Barsky Flashcards

1
Q

What are mesenchymal cancers called?

A

Sarcomas

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2
Q

What are epithelial cancers called?

A

Carcinomas

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3
Q

Are epithelial cancers more common than mesenchymal cancers?

A

Yes

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4
Q

What is the ‘multi hit’ theory?

A

This theory states that human cancers take time to develop. A single cell has to go through many ‘hits’ or steps to become malignant.

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5
Q

Name some events related to tumor progression.

A
  1. genetic - mutations, rearrangements, amplification of pro to-oncogenes, reduction to homozygosity of tumor suppressor gene deletions or mutations
  2. epigenetics
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6
Q

Why is cancer a disease of aging?

A

Most cancers are multi hit events - it takes time for a single cell to get multiple hits

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7
Q

What must happen for cancer cells to spread?

A

They must have access to lymphatics or blood vessels and these are not located on the epithelial side of the basement membrane.

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8
Q

Name the properties of cancer.

A
  1. uncontrolled growth
  2. invasion and metastasis
  3. clonal dominance
  4. loss of differentiation
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9
Q

What is meant by the statement - human cancers are monoclonal?

A

Human cancers are derived from a single ancestral cell. This is also referred to as clonal dominance.

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10
Q

Describe tumor progression and heterogeneity.

A
  1. a single tumor cell develops
  2. tumor cells divide and become a population
  3. as the tumor cells increase there are a subset that develop different traits - this is referred to as heterogeneity
  4. mutant sub clones are heterogenous with respect to invasiveness, metastatic ability, antigenicity and responsiveness to chemotherapy
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11
Q

Name some general categories of cancer therapy.

A
  1. surgery
  2. radiotherapy
  3. chemotherapy
  4. immunotherapy
  5. gene therapy
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12
Q

What are some limitations in treating cancer?

A
  1. lack of a tumor specific antigen (some exceptions) - cancer is a disease of our own cells
  2. tumor cell heterogeneity - tumors grow and they change at the cellular level
  3. micrometastasis - tumor cells invade and spread and this is an early event in cancer and makes treatment harder
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13
Q

What are the etiologies of cancer?

A
  1. the vast majority have unknown causes
  2. UV radiation - can cause cancer of the skin
  3. other ionizing radiation - such as on the job sources
  4. viruses
  5. lifestyle, diet, immune status
  6. hereditary factors or genes
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14
Q

What is the MOA of chemical carcinogens?

A

Forms DNA adducts that give rise to mutations. If mutation occurs in a spot that changes gene expression or protein expression mutations can be carcinogenic. DNA adducts are formed by the binding of an initiator of the chemical carcinogen to the DNA.

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15
Q

What are initiators?

A

Initiators are chemical carcinogens that interact with DNA and lead to mutations. They are often electrophilic.

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16
Q

What are promoters?

A

Once a cell has mutated (undergone initiation) it is susceptible to promotors. These are compounds that promote proliferation of the cell. They are often electrophiles also and they can be passed on to progeny cells.

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17
Q

Which of our body’s enzymes regulates chemical carcinogens?

A

Phase 1 and Phase II enzymes.

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18
Q

How do UV radiation and other types of ionizing radiation cause cancer?

A

They form adducts with DNA, leading to mutation. They can also cause chromosome breakage, translocations and point mutations.

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19
Q

UV radiation leads to what type of cancer?

A

Skin cancer. Those with the condition xeroderma pigmentosum are at increased risk.

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20
Q

Give a couple of examples where radiation has been known to cause cancer.

A
  1. 9% of kids exposed to childhood irradiation develop thyroid cancer.
  2. nuclear radiation from bombing of Hiroshima and Nagasaki
  3. nuclear radiation from above ground bomb testing in Nevada
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21
Q

Name three viruses associated with cancer.

A
  1. HPV
  2. EBV
  3. Hep B virus
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22
Q

Describe HPV.

A
  1. HPV is the human papilloma virus
  2. there are 80+ pathotypes
  3. 1,2,3,4 and 7 cause papillomas or warts
  4. 16 and 18 are associated with almost 100% of invasive squamous cell carcinoma and carcinoma in-situ of the cervix
  5. 6 and 11 have low malignant potential
  6. E6 and E7 are early gene products of HPV that inactivate tumor suppressor genes TP53 and RB respectively
  7. full malignant potential requires other environmental factors not just exposure to virus
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23
Q

Describe EBV.

A

Associated with 4 types of tumors:

  1. B cell lymphomas in immunosuppressed
  2. Hodgkin’s disease
  3. Nasopharyngeal cancer - endemic in S. China
  4. Burkitt’s lymphoma - associated with MYC gene (translocation gene involving chromosomes 8 and 14)
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24
Q

Describe the Hep B virus.

A
  1. contributes to hepatocellular cancer (multifactorial)
  2. HBx protein greatly disrupts growth control by activating protooncogenes, may inactivate TP53
  3. injury and regeneration predispose to mutations with environmental agents
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25
Q

How does immune status contribute to cancer?

A

Immunodeficient hosts have a higher rate of certain cancers like lymphoma and virally induced cancers. Their immunodeficient states leave the body unable to fulfill its normal role in clearing some cancer associated microbes/cells.

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26
Q

How does lifestyle affect susceptibility to cancer?

A

The mechanisms are unknown but associations between certain lifestyle choices such as sun tanning, promiscuity and obesity are associated with cancers.

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27
Q

Give some examples of lifestyle choices and the cancers they are associated with.

A
  1. suntanning - skin cancer
  2. promiscuity - cervical cancer
  3. nulliparous women - breast cancer
  4. obese men - cancer of esophagus
  5. women who eat fatty foods - breast cancer
  6. men who drink alcohol and smoke - head and neck cancer
  7. people who eat red meat - colon cancer
28
Q

How does heredity factor into cancer?

A

Some cancers are inherited and the associated gene may or may not be identified. Many cancers have a familial component but only a few have an inherited component.

29
Q

Name some factors that contribute to hereditary cancers.

A
  1. defective P53 gene is associated with Li-Fraumeni syndrome
  2. BRCA1 and BRCA2 genes are associated
  3. micro-satellite instability genes are associated with Lynch syndrome
  4. Retinoblastoma is associated with an inherited RB gene
30
Q

If you lack risk factors does that mean you are safe from developing cancer?

A

No, most cancers are spontaneous and sporadic and the cause is unknown.

31
Q

What are two key properties of cancer?

A
  1. growth in an uncontrolled manner

2. invasion and metastasis

32
Q

What are oncogenes?

A

These are genes that code for products (oncoproteins) associated with neoplastic transformation. They are not regulated by normal growth factors and signals.

33
Q

What are protooncogenes?

A

These are normal genes that affect growth and differentiation such as v-oncs (involved in retroviral transduction). These genes can undergo changes in situ which convert them to oncogenes.

34
Q

How are protooncogenes activated or turned into oncogenes?

A
  1. point mutations - RAS most common
  2. chromosomal translocation - moved near promoter or chimeric gene product
  3. gene amplification - ie. N-MYC gene in neuroblastoma, HER-2 gene in breast carcinoma
35
Q

What are the five basic categories of oncogenes?

A
  1. growth factors
  2. growth factor receptors
  3. signal transducing proteins
  4. nuclear transcription factors
  5. cyclins and cyclin dependent kinases
36
Q

What are antioncogenes?

A

These are cancer suppressor genes. They often code for products that suppress cell proliferation.

37
Q

How can cancer be promoted?

A
  1. inactivation of genes - loss of function

2. gain of function in oncogenes

38
Q

Name some antioncogenes.

A
  1. growth inhibitory factors
  2. molecules that regulate cell adhesion
  3. molecules that regulate signal transduction
  4. molecules which regulate nuclear transcription and cell cycle
39
Q

Describe TP53.

A
  1. a tumor suppressor gene
  2. one of the most commonly mutated genes seen in virtually all types of human cancers
  3. it codes for products involved in anti proliferation and apoptosis
40
Q

Name some functions of TP53.

A
  1. TP53 senses DNA damage and arrests the cell in G1 to induce DNA repair
  2. TP53 increases CDK1 preventing phosphorylation of RB
  3. TP53 induces GADD45 which aids in DNA repair
  4. if DNA cannot be repaired apoptosis genes such as BAX are induced
41
Q

Describe Li Fraumeni syndrome.

A
  1. associated with inheritance of one mutant TP53 or RB gene
  2. associated with marked increase in risk of multiple types of malignancies
  3. progression to cancer requires mutation of the second normal allele
  4. the second normal allele can be inactivated by certain DNA viruses such as HPV, HBV and possibly EBV
42
Q

What gene is associated with childhood tumor retinoblastoma?

A

The RB gene. If you inherit one mutant allele ( 40% familial because autosomal dominant and 60% of cases are sporadic) then you are at risk for certain malignancies.

43
Q

Describe the famous ‘two hit’ retinoblastoma hypotheses.

A
  1. two normal RB loci requires both genes to be inactivated by somatic mutation
  2. if you inherit one mutant gene then you only need ‘one hit’ to knock out the other normal allele
  3. increases the risk of sarcomas, including osteosarcomas
44
Q

How are epigenetics associated with cancer?

A
  1. many cancer genes are regulated epigenetically
  2. methylation status and histone deacytylase status within promoters regulate gene expression of key cancer genes
  3. cancer is characterized by methylation and histone deacytylation imbalance
45
Q

What is the definition of cancer invasion?

A

Active migration of neoplastic cells out of their tissue of origin and across host tissue boundaries.

46
Q

What is the definition of a metastasis?

A
  1. A secondary tumor colony discontinuous from the primary tumor
  2. arising from a tumor cell translocated from the primary tumor
47
Q

What must invading cancer cells be able to do to metastasize?

A

They must be able to access circulation (intravasation) and must be able to extravasate or get out of circulation. They must also be able to survive in the new tissue.

48
Q

What is one factor that may cause mesenchymal tumors to metastasize more easily than epithelial tumors?

A

The epithelial cancer cells must break through the basement membrane to gain access to circulation while mesenchymal tumors arise in the mesenchyme and potentially have access to circulation.

49
Q

What are the 3 main routes that neoplasms use to metastasize?

A
  1. lymphatic spread - regional lymph nodes are usually affected first
  2. hematogenous spread - this is spread via the circulatory system - the lung, liver, brain, adrenals and bone marrow are often sites of metastasis
  3. transcoelomic spread - seeding of body cavities such as peritoneal, pleural, pericardial and subarachnoid spaces
50
Q

Describe how carcinomas and lymphomas tend to spread.

A

Carcinomas tend to spread thru lymphatics and lymphomas tend to spread hematogenously but this is not a hard and fast rule.

51
Q

What is grading in reference to cancer?

A

Grading a cancer has to do with the degree of loss of differentiation of cancer cells. Normal cells differentiate but cancer cells lose this ability. Well differentiated cancers have not progressed as much. Grading is done by looking at the appearance of cancer cells under a microscope.

52
Q

What is staging in reference to cancer?

A

Staging is a measurement of invasion and metastasis. This the anatomic extent of a tumor. Two staging systems are the TMN and the AJC.

53
Q

Describe the TMN staging system.

A
  1. T - refers to
  2. N - refers to lymph node involvement
  3. M - refers to the presence of documented metastasis
54
Q

What must happen for invasion of tumor cells?

A
  1. cells must become less cohesive - ie. E-cadherins are reduced
  2. tumor cells must attach to matrix components - ie. laminin and fibronectin
  3. the ECM must be degraded - ie. can occur with metalloproteinases, collagenases and plasmin
  4. there must be vascular dissemination and homing of tumor cells - ie. can form emboli with leukocytes and platelets or circulate as single cells
55
Q

What factors affect the eventual site of metastasis of cancer cells?

A
  1. organ tropism
  2. vascular and lymphatic drainage
  3. tumor adhesion molecules may enhance attachment to tissue ligands
  4. microenvironment such as proteases may inhibit attachment
56
Q

What is the Soil Seed Hypothesis of Paget?

A

The idea that cancer cells exhibit tropism - they tend to grow in certain organs.

57
Q

Is metastasis an early event in cancer development? How do we know?

A

Yes. We know this because tumor cells can be found circulating in blood - they are called CTS’s.

58
Q

What is a disseminated tumor cell or DTC?

A

This a cell that is found where it does not belong. DTC’s must have been circulating tumor cells at one point. Just the presence alone of a DTC does not mean that metastasis has occurred. The DTC must be able to survive and grow in the new tissue, it must contain cancer stem cells.

59
Q

What are cancer stem cells?

A

These are populations of tumor cells that are capable of repopulating the tumor. Chemotherapy clears proliferating cancer cells but not necessarily the stem cells. Cancer stem cells come from genes involved in cell division/cell dysregulation such as P53 and RB. The genes involved with invasion and metastasis are unknown.

60
Q

Name the different types of stem cells.

A
  1. embryonic stem cells
  2. induced pluripotent stem cells
  3. adult or somatic stem cells
  4. stem cells in tissue homeostasis
  5. cancer stem cells
61
Q

What are essential properties of all stem cells including cancer stem cells?

A
  1. self renewal - can make copies of itself
  2. can undergo symmetrical and asymmetrical cell division - can make cells that can differentiate
  3. exhibit pluripotency
62
Q

Name some properties of cancer stem cells.

A
  1. exist in a resting or dormant state
  2. resist chemotherapy and radiotherapy
  3. express embryonic stem cell pathways
  4. replenish the dividing cell population of the tumor
63
Q

What are some pathways involved in stem cell self renewal?

A
  1. Hedgehog
  2. Notch
  3. Bmi-1
  4. Wnt
  5. Pten
64
Q

What two markers are associated with cancer stem cells?

A
  1. CD44+

2. CD24-

65
Q

What are the implications of cancer stem cells for treatment?

A

If we could develop drugs that kill cancer stem cells and cancer cells then tumors would lose the ability to generate new cells and new stem cells and the tumor would degenerate and the patient would be cured. Drugs that kill only cancer cells can lead to tumor regression but tumors may recur.

Block 7 week 1 (3 decks)

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