Hallmarks of Cancer II

Question 1

Cancer: Evasion of Apoptosis

Answer 1

Apoptosis can be initiated either through extrinsic or intrinsic pathways, and abnormalities are found in both pathways in cancer cells, though intrinsic is most common.

Question 2

General ways cancer has limitless replicative potential

Answer 2

1) Some cells in cancer are always stem-like, either because an actual stem cell is affected, or because a genetic lesion imparts a stem-like ability.
2) Cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase, which act together to convey limitless replicative potential.

Question 3

Hypoxia, Angiogenesis, and Cancer

Answer 3

1) A tumor needs to be vascularized in order to survive.
2) Hypoxia of the cancer triggers angiogenesis via HIF-1-alpha, which interacts with VEGF. (This means that many cancers are treated, though not cured, with VEGF inhibitors)
3) p53 regulates angiogenesis by inducing the synthesis of angiogenesis inhibitor thrombospondin-1

Question 4

Angiogenesis inhibitor thrombospondin-1

Answer 4

Produced by p53 in an attempt to control angiogenesis of tumors.

Question 5

Signaling dudes that up-regulate VEGF expression

Answer 5

RAS
MYC
MAPK

These all stimulate angiogenesis.

Question 6

______________ has displaced squamous cell carcinoma as the most common type.

Answer 6

Adenocarcinoma.

1) Seen in higher percentages of non-smokers, women, and Asians.
2) Seen in higher percentages of peripheral lung cancer.

Why? Theorized that pollution plays a role. Also that cigarettes filter only large particles that typically would get stuck in the central airway, allowing the smaller ones to escape to the periphery of the lungs.

Question 7

Bronchioloalveolar carcinoma (BAC)

Answer 7

The name for pulmonary adenocarcinoma in situ.

Recall that carcinoma in situ means that the tissue has all of the cytologic features of malignancy without visible invasion.

Question 8

Atypical adenomatous hyperplasia (AAH)

Answer 8

The precursor to PULMONARY adenocarcinoma

The same thing as “dysplasia”

Question 9

Metastases

Answer 9

Process:

1) An alteration in intracellular adhesion molecules (e.g. E-cadherin) allows dissociation of cancer cells from each other [LOOSENING OF CELL-CELL CONTACTS]
2) Carcinoma breaches the basement membrane either by secreting their own proteolytic enzymes or getting other cells to do so [DEGRADATION OF ECM]
3) Then, tumor cells attach to ECM proteins; when MMPs cleave collagen IV and laminin, new sites that bind to tumor cells appear and stimulate migration [ATTACHMENT TO NOVEL ECM COMPONENTS]
4) Tumors secrete cytokines like autocrine motility factors that direct migration [MIGRATION OF TUMOR CELLS]

Question 10

E-cadherins

Answer 10

Mediate the HOMOTYPIC adhesion of epithelial cells and relay signals between cells to maintain contact inhibition and prevent abnormal growth. When a cancer cell degrades the basement membrane, it is ruining the cell-cell adhesion created by E-cadherins.

Question 11

Proteases that aid in degradation of the basement membrane when a cancer cell is attempting to escape

Answer 11

MMPs (matrix metallo-proteinases), cathepsin D, and urokinase plasminogen activator.

These are part of normal cellular response to injury, but cancer cells can release these same proteases with malicious intent; that is, they release the proteases (and encourage other cells around them to do so as well) in order to escape into the bloodstream and metastasize.

Question 12

MMP9

Answer 12

A gelatinase that cleaves Type IV collagen of the epithelial and vascular basement membrane and stimulates the release of VEGF from ECM-sequestered pools. Cancer uses this molecule to its advantage - it secretes it (and encourages surrounding cells to secrete it) so that it can escape into the bloodstream once the collagen and basement membrane are no longer present.

Question 13

Stromal cells and metastasis

Answer 13

Stromal cells can produce paracrine effectors to initiate cell motility.

E.g. Hepatocyte growth factor/scatter factor binds to MET on tumor cells, helping with motility. MET is a tyrosine kinase pathway that can be up-regulated and/or used to bypass targeted drug therapy.

Question 14

Tumor cell behavior in circulation, and their motivation for said behavior

Answer 14

Tumor cells aggregate in clumps because of their homotypic adhesions and because of their ability to bind to blood cells, particularly platelets. They can also cause formation of emboli by binding coagulation factors.

Motivation: Formation of platelet-tumor aggregates may enhance tumor cell survival and implantability.

Question 15

CD44

Answer 15

Normally used by T-cells to bind to hyaluronate on HEVs in order to extravasate into lymphoid tissues

Used by solid tumors to enhance their spread to lymph nodes and other metastatic sties

Question 16

Causes for characteristic patterns of metastases

Answer 16

1) Drainage pathways
2) Organ tropism

The site at which circulating tumor cells leave capillaries is related to the anatomic location and vascular drainage of the primary tumor, as well as the tropism of particular tumors for specific tissues.

Question 17

Metastatic organ tropism: Its determinants

Answer 17

The characteristic patterns of metastasis are due to drainage pathways and organ tropism.

Organ tropism: Various organs will express varying concentrations of endothelial cell ligands for adhesion molecules. A cancer cell finds the environment (ligands) it likes best. It seems that not many cancer cells enjoy muscle or spleen tissue.

For example, CXCR4 and CCR7 chemokines are receptors heavily utilized by breast cancers, whereas other chemokines might encourage development of lung cancer

Question 18

Where do prostatic carcinomas prefer to spread?

Answer 18

Bone

Question 19

Where do small cell carcinomas prefer to spread?

Answer 19

Liver and adrenals

Question 20

Where to neuroblastomas prefer to go?

Answer 20

Liver and bones

Question 21

How do cancer cells turn a site into their new home?

Answer 21

They can secrete cytokines, growth factors, and ECM molecules on resident stromal cells, which in turn make the site habitable for the cancer cell.

Question 22

How does breast cancer spread to bone?

Answer 22

1) Breast cancer cells secrete parathyroid hormone-related protein (PTHRP)
2) PTHRP stimulates osteoblasts to make RANK ligand (RANKL)
3) RANKL activates osteoclasts, which degrade the bone matrix and release growth factors embedded within it, like IGF and TGF-B

Question 23

SNAIL and TWIST

Answer 23

Metastatic oncogenes that encode transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). One way they achieve this is through acting as repressors that down-regulate E-cadherin expression. The changes favor the development of a pro-migratory phenotype essential for metastasis.

Basically, if a cancer cell is lucky enough to have SNAIL and TWIST, it can down-regulate E-cadherin and initiate the others processes (release of MMPs, etc) that allow it to metastasize to another site in the body.

Question 24

How does a cancer cell become pro-migratory?

Answer 24

It down-regulates epithelial markers like E-cadherin and up-regulates mesenchymal markers like vimentin.

Question 25

EMT

Answer 25

Seen mostly in breast cancer

Stands for “epithelial-to-mesenchymal transition”

Key event in EMT is the loss of E-cadherin, which greatly helps with migration of tumor cells to a secondary site.

Question 26

Hereditary nonpolyposis colon cancer (HNPCC)

Answer 26

An autosomal dominant disorder characterized by familial carcinomas of the colon

Occurs due to defects in a family of genes that encode proteins that engage in DNA mismatch repair

Affected individuals inherit one abnormal copy of mismatch repair gene, then cells acquire a loss-of-function mutation that knocks out the other allele. Mutations slowly mount that could end up activating proto-oncogenes or inactivate tumor suppressor genes, in time leading to cancer

Question 27

Defective DNA-repair genes

Answer 27

These have the same mode of inheritance as tumor suppressor genes (in the way that a person is born with one good allele and one bad), but they affect cell growth only indirectly by allowing mutations to accumulate.

They are enablers of cancer.

Question 28

Microsatellite instability

Answer 28

A hallmark of patients with mismatch-repair defects

They are tandem repeats of 1-6 nucleotides are found throughout the genome. In normal people, that length parameter remains constant.

In affected individuals, the length does not remain constant in some cells. These abnormal cells create alleles not found in unaffected cells of the same patient.

Question 29

Mismatch repair genes involved in pathogenesis of HNPCC

Answer 29

Germline mutations in MSH2 and MLH genes

Account for 30% of cases.

Question 30

Cancer genes mutated in HNPCC

Answer 30

1) Genes encoding TGF-beta receptor II
2) TCF component of the B-catenin pathway
3) BAX

Question 31

BRCA 1 and 2

Consequence of mutations

Purpose for existence

How they’re unique

Answer 31

BRCA1 and 2 account for 25% of FAMILIAL breast cancer

BRCA1 mutations increase the risk of epithelial ovarian cancers

BRCA2 mutations increase the risk of breast cancer in men and women, as well as cancer of the ovary, prostate, pancreas, bile ducts, stomach, melanocytes, and B lymphocytes

BRCA proteins form a DNA-damage response network in order to repair certain types of DNA damage using the homologous recombination repair pathway. Defects in the DNA damage system lead to dicentric chromosomes, massive aneuploidy, bridge-fusion-breakage cycles, etc.

BRCA1 and 2 are rarely inactivated in SPORADIC cancers; this is different from tumor suppressor genes like p53, which is inactivated in BOTH sporadic and familial cancers

Question 32

Are persons with inherited mutations of genes involved in DNA repair systems at a greatly increased risk for the development of cancer?

Answer 32

Yes.