Path: Hallmarks of Cancer 2

Question 1

Apoptosis can be initiated through intrinsic or extrinsic pathways, both of which result in the activation of a proteolytic cascade of _________ that destroys the cell.

Answer 1

caspases

Question 2

Abnormalities of the intrinsic or extrinsic pathways of apoptosis appear to be the most common causes of cancer?

Answer 2

intrinsic (mitochondrial)

Question 3

At least some cells in all cancers must be _______-cell like.

Answer 3

stem-cell

Question 4

How do the cancer stem cells arise?

Answer 4

through transformation of normal stem cells or through acquired genetic lesions that impart a stem-like state on a more mature cell

Question 5

Cancer cells acquire lesions that inactivate senescence signals and reactivate _______ (enzyme), which act together to convey limitless replicative potential.

Answer 5

telomerase

Question 6

Vascularization of tumors is essential for their growth and is controlled by the balance between ________ and _______ factors that are produced by tumor and stromal cells.

Answer 6

angiogenic; anti-angiogenic

Question 7

Hypoxia triggers angiogenesis through the actions of ________ on the transcription of the proangiogenic factor _________.

Answer 7

HIF-1a; VEGF

Question 8

How does p53 regulate angiogenesis?

Answer 8

By inducing synthesis of the angiogenesis inhibitor thrombospondin-1.

Question 9

Is p53 a pro or anti-angiogenic factor?

Answer 9

anti

Question 10

Signaling of RAS, MYC, and MAPK all up/downregulate (?) VEGF expression and stimulate/inhibit (?) angiogenesis?

Answer 10

Upregulate; stimulate

Question 11

VEGF inhibitors are used to treat a number of advanced cancers and prolong the clinical course. Are they curative?

Answer 11

No.

Question 12

What type of cancer has displaced squamous cell carcinoma as the most common type of primary lung cancer?

Answer 12

Adenocarcinoma

Question 13

Pulmonary adenocarcinoma in situ has a unique special name:

Answer 13

bronchioalveolar carcinoma (BAC)

Question 14

What is the precursor to pulmonary adenocarcinoma?

Answer 14

atypical adenomatous hyperplasia (AAH)

Question 15

Atypical adenomatous hyperplasia is the same thing as metaplasia or dysplasia?

Answer 15

dysplasia

Question 16

What is the first step in invasion of surrounding tissue by a malignant tumor?

Answer 16

Dissociation of cancer cells from one another- often the result of alterations in intercellular adhesion molecules, for example: E-cadherin

Question 17

Cell-cell interactions are mediated by the ______ family of transmembrane glycoproteins.

Answer 17

cadherin

Question 18

________ mediated the homotypic adhesion of epithelial cells, serving to both hold the cells together adn to relay signals between the cells, maintaining contact inhibition on abnormal cell growth.

Answer 18

E-cadherins

Question 19

Describe the step following ECM and BM remodeling in tumor invasion.

Answer 19

changes in attachment of tumor cells to ECM proteins. Cleavage of the CM proteins collagen IV and laminin by MMP2 and MMP9 generates novel sites that bind to receptors on tumor cells and stimulate migration. Less binding to cells they are normally adhered to, more binding to cells they should not adhere to, but that help them migrate deeper into tissues, away from where they belong.

Question 20

What is the final step of invasion by malignant tumor cells?

Answer 20

Locomotion, propelling tumor cells through the degraded BM and zones of matrix proteolysis.

Question 21

Movement of tumor cells through the ECM and past the BM is stimulated and directed by tumor-derived cytokines, such as:

Answer 21

autocrine motility factors.

Question 22

Cleavage products of matrix components (e.g. collagen, laminin) and some growth factors (e.g. IGFs I and II) have _________ activity for tumor cells.

Answer 22

chemotactic

Question 23

Describe how tumor cells interact with one another and blood products in circulation.

Answer 23

They clump together (homotypic adhesion). Also clump with platelets (heterotypic adhesion)

Question 24

Formation of _____-tumor aggregates in circulation may enhane tumor cell survival and implantability.

Answer 24

platelet-tumor aggregates

Question 25

What adhesion molecules do tumor cells use to adhere to endothelium and extravasate at distant sites during metastasis? What to they use to extravasate and pass through the BM of blood vessels and the underlying connective tissue?

Answer 25

integrins, laminins; Proteolytic enzymes

Question 26

What adhesion molecule to solid tumor cells often share in common with T lymphocytes which appears to enhance their spread to lymph nodes and other metastatic sites?

Answer 26

CD44

- used by T lymphocytes normally to migrate to selective sites in lymphoid tissue

Question 27

Characteristic patterns (e.g. colon to liver, prostate and breast to bone) are due to ________ pathways and organ tropism. What is organ tropism?

Answer 27

Drainage pathways.

Tropism: Differential concentration of endothelial cell ligands for adhesion molecules in different organs

Question 28

What two factors determine the site at which circulating tumor cells leave the capillaries to form secondary deposits?

Answer 28

1) anatomic location/vascular drainage of the primary tumor

2) tropism of particular tumors for specific tissues

Question 29

T/F: most metastases occur in the 1st capillary bed available to the tumor.

Answer 29

True

Question 30

Do natural pathways of drainage wholly explain the distribution of metastases?

Answer 30

No. Organ tropism will account for many variations from this rule.

Question 31

Describe a few examples of organ tropisms that account for variance from anatomic/drainage/1st capillary bed rules of metastasis.

Answer 31

1) tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ
2) chemokines have an important role in determining the target tissues for metastasis (some breast cancer cells express the chemokine receptors CXCR4 and CCR7)
3) in some cases, the target tissue may be a non-permissive environment for the growth of tumor seedings (e.g. skeletal muscle, spleen are rare sites of metastasis)

Question 32

What two factors determine the site at which circulating tumor cells leave the capillaries to form secondary deposits?

Answer 32

1) anatomic location/vascular drainage of the primary tumor

2) tropism of particular tumors for specific tissues

Question 33

T/F: most metastases occur in the 1st capillary bed available to the tumor.

Answer 33

True

Question 34

Do natural pathways of drainage wholly explain the distribution of metastases?

Answer 34

No. Organ tropism will account for many variations from this rule.

Question 35

Describe a few examples of organ tropisms that account for variance from anatomic/drainage/1st capillary bed rules of metastasis.

Answer 35

1) tumor cells may have adhesion molecules whose ligands are expressed preferentially on the endothelial cells of the target organ
2) chemokines have an important role in determining the target tissues for metastasis (some breast cancer cells express the chemokine receptors CXCR4 and CCR7)
3) in some cases, the target tissue may be a non-permissive environment for the growth of tumor seedings (e.g. skeletal muscle, spleen are rare sites of metastasis)

Question 36

How do tumor cells influence resident stromal cells to make the metastatic site habitable for the cancer cell?

Answer 36

Tumor cells secrete cytokines, growth factors, and ECM molecules that act on the resident stromal cells.
e.g. breast cancer cells secrete PTH-related protein, which stimulates osteoblasts to make RANKL, which activates osteoclasts to breakdown bone matrix and release growth factors embedded within it = good for the newly established tumor cells.

Question 37

What are SNAIL and TWIST and what implications do they have for metastasis?

Answer 37

metastasis oncogenes, which encode transcription factors whose primary function is to promote epithelial-to-mesenchymal transition (EMT). In EMT, carcinoma cells downreg. certain epithelial markers (E-cadherin) and upreg. certain mesenchymal markers (vimentin and smooth muscle actin). These changes are believed to favor the development of a promigratory phenotype that is essential for metastasis.

Question 38

SNAIL and TWIST are transcriptional repressors that have what influence on E-cadherin expression?

Answer 38

downregulate

Question 39

What is microsatellite instability?

Answer 39

Microsatellites are tandem repeats of one to six nucleotides found throughout the genome. In normal people, the length of these microsatellites remains constant. Not when they are “unstable”. When they are unstable, they can mess with genes such as those encoding TGF-B receptor II, TCF component of the B-catenin pathway, BAX, and other oncogenes and tumor suppressor genes.

Question 40

Mutations in _______ and ______ account for 25% of cases of familial breast cancer.

Answer 40

BRCA1 and BRCA2

Question 41

In addition to breast cancer, women with BRCA1 mutations, have a substantially higher risk of ________ ________ cancers and men have a slightly higher risk of ________ cancer.

Answer 41

epithelial ovarian cancers; prostate cancer

Question 42

T/F: mutations in the BRCA2 gene increase the risk of breast cancer in both men and women, as well as many other cancers.

Answer 42

True

Question 43

What is the job of the BRCA genes?

Answer 43

BRCA genes encode for BRCA proteins that form a DNA-damage response network whose purpose is to repair certain types of DNA damage using homologous recombination repair pathway.

Question 44

What happens when normal BRCA genes are absent?

Answer 44

Defects in their normal function (DNA repair) lead to the activation of the salvage nonhomologous end joining pathway and formation of dicentric chromosomes, bridge-fusion-breakage cycles, and massive aneuploidy.

Question 45

Why are pts with xeroderma pigmentosum at increased risk for the development of cancers of the skin exposed to UV light?

Answer 45

They have a defect in the nucleotide excision repair pathway and thus have an inability to repair pyrimidine dimers caused by exposure to UV light.

Question 46

Syndromes involving defects in the homologous recombination DNA repair system constitute a group of disorders- _______, ________, and _______- that are characterized by hypersensitivity to DNA-damaging agents, such as ionizing radiation.

Answer 46

Bloom syndrome, ataxia-telangiectasia, and Fanconi anemia.