T&H10 Tumor progression and metastasis

Question 1

What is the rate limiting step in tumor progression and metastasis?

Answer 1

breakdown of ECM integrity

Question 2

Increased _____- mediated activity brings about remodeling of the ECM and basement membrane and influences cell adhesion by cadherins.

Answer 2

MMP

Question 3

Loss of ____ can promote EMT in cells.

Answer 3

E-cadherin

Question 4

What are the four major classes of proteinases? List examples of each that have been associated with malignancy and list their inhibitors.

Answer 4

1. MMPs
   - Example: ADAMS
   - Inhibitors: TIMPs
2. Serine proteases
   - Example: plasminogen activators (uPA and tPA) and kallikreins
   - Inhibitors: PAIs
3. Cysteine proteinases
   - Example: Cathepsins B, L, and H
   - Inhibitors: kinogens, cystatins, stefins
4. Aspartic proteinases
   - Example: Cathepsins D
   - No known inhibitor

Question 5

Tumor cells break through a number of tissue barriers during invasion and metastasis via processes involving ______________.

Answer 5

proteolytic breakdown of the ECM

Question 6

________ are a group of proteases acts as sheddases that release cell surface growth factors and cytokines (ectoderm shedding) and are implicated in activation of _____ and ______ signaling pathways.

Answer 6

• ADAMs family of MMPs
• NOTCH and EGFR

Question 7

_____ are a type of serine proteinase that are best known for being a biomarker for prostate cancer progression (PSA).

Answer 7

Kallikreins

Question 8

_______ are types of serine proteinases that act on plasminogen to release plasmin.

Answer 8

urokinase type and tissue type plasminogen activators (uPA and tPA)

Question 9

Plasminogen and plasmin activity is localized to the cell surface by __________, which associates with _____ and can bind to vitronectin in the ECM.

Answer 9

• uPA receptor (uPAR)
• Integrins

Question 10

Increased uPA expression has been correlated with metastasis in a number of cancers, including ______________.

Answer 10

HER2+ breast cancer

Question 11

Cathepsins, particularly ___, ___, and ___ have been associated with tumor progression.

Answer 11

B, H, and L

Question 12

_____ make up a group of transmembrane receptors for proteins of the ECM (ie, fibronectin, laminin, vitronectin, collagens)

Answer 12

integrins

Question 13

The cytoplasmic domain of the ____ subunit of integrins interacts directly with components of the ____________, allowing its localization to ____________ that form at points of contact between integrins and ECM.

Answer 13

• Beta
• actin cytoskeleton
• focal adhesion plaques (FAPs)

Question 14

________ interaction plays a role in ECM signaling in primary tumor cells when they first migrate to other organs and thus promote metastasis.

Answer 14

a3B1-FAK

Question 15

______ are intercellular adhesion molecules important for assembling adhesion junctions and desmosomes.

Answer 15

cadherins

Question 16

______ are cellular proteins that link cadherins to actin skeleton and to signal transduction components.

Answer 16

catenins

Question 17

APC tumor supressor gene and B-catenin form physiological complexes with ____ and ____. B-catenin can be phosphorylated by ____ and targeted for ubiquitin-mediated degradation, which acts to control the level of B-catenin the the cell.

Answer 17

• axin and glycogen synthase kinase (GSK) - 3B
• GSK-3B

Question 18

If not targeted for degradation, B-catenin can enter the nucleus and associated with LEF/TCP transcription factors to upregulate genes involved with cell growth, such as ____ and _____.

Answer 18

c-myc and cyclin D1

Question 19

Mutations in ___ lead to truncated forms and are unable to bind to B-catenin, which results in reduced degradation.

Answer 19

APC

Question 20

Degradation of B-catenin can be disrupted if ______ is blocked by activation of the WNT pathway.

Answer 20

GSK-3B

Question 21

____ is a cell surface glycoprotein and major receptor that mediates cellular interactions with hyaluronate. Its principle function is the aggregation, migration, and activation of cell functions.

Answer 21

CD44

Question 22

_____ contains a cytoplasmic domain that may link to actin filaments through interactions with ankyrin, ezrin, and moesin. Many of its isoforms are overexpressed in many tumors.

Answer 22

CD44

Question 23

________, a secreted glycoprotein implicated in invasion and metastasis, binds to CD44 and may play a role in malignancy-promoting potential.

Answer 23

osteopontin

Question 24

______ is a metastasis associated gene that is related to prognosis in a number of cancers. It connects actin skeleton to cell membrane.

Answer 24

ezrin

Question 25

Tumor cells in hypoxic regions can express ______ to initiate angiogenesis process to compensate for lower nutrient and oxygen supplies.

Answer 25

HIFs

Question 26

_____ are molecules used by leukocytes to home specific organs and may play a role in organ specificity for metastasis.

Answer 26

chemokines

Question 27

Human breast cancer cells have high expression of chemokine receptors (______, _______) while their respective ligands are highly expressed in organs which breast cancer cells have a high propensity to form metastases (lung, liver, regional lymph nodes, and bone marrow).

Answer 27

CXCL12, CCL21

Question 28

The most common cell-surface protein for circulating tumor cell detection is ____.

Answer 28

EpCAM

Question 29

What growth factors can induce vascular remodeling and facilitate intravasation?

Answer 29

VEGF and FGF

Question 30

Detachment of cancer cells from the primary tumor may involve decreased expression of adhesion molecules involved in "homotypic" adhesion of cells to one another or may depend on expression of motility factors, such as ______, _____, or _____.

Answer 30

HGF, autotoxin, or autocrine motility factor

Question 31

Tumor cells sometimes travel with ____ in the bloodstream to evade immune surveillance.

Answer 31

platelets

Question 32

What is a reason why so many mets are detected in lungs or liver?

Answer 32

Most tumor cells arrest in first capillary bed they encounter (first-pass bed)

Question 33

Extravasation involves a variety of proteases with ____ playing a major role.

Answer 33

MMPs

Question 34

Bone tumors secrete ______, _____, and _______ which causes release of _______ by osteoblasts. This stimulates myeloid progenitor cells to differentiate into osteoclasts to create a space for metastasis,

Answer 34

- PTHrP, IL-6, and TNFa - receptor activator of nuclear factor -kB ligand (RANKL)

Question 35

_______ was shown to reduce macrometastasis but was ineffective against dormant tumor cells.

Answer 35

Doxorubicin

Question 36

A number of factors, like _____ and ____, have been implicated in reactivating dormant tumor cells.

Answer 36

VEGF and Id1

Question 37

_______ is the dominant protease mobilized for cancer cell trafficking through 3D interstitial ECM barriers.

Answer 37

MT1-MMP

Question 38

MMPs can cleave _____, which promotes bone mets.

Answer 38

RANKL

Question 39

MMPs play multiple roles in tumor progression and metastasis, including ______, __________, _____________, and _______.

Answer 39

angiogenesis, inflammation regulation, tissue extravasation and intravasation, and creating a metastatic niche.

Question 40

_____ is a critical activator for cancer associated fibroblasts.

Answer 40

TGF-B

Question 41

The inflammatory states of tumor associated macrophages are controlled by the transcription factor, ______, which in turn is activated through _____ receptors.

Answer 41

- NF-KB - toll-like receptors

Question 42

Tumor associated macrophages exert most of their inflammatory effects via cytokines, such as ___.

Answer 42

IL-6

Question 43

The cytokine _____ can make tumor vessels leaky, leading to the recruitment of more inflammatory cells and provides exit for tumor cells to then escape into the bloodstream.

Answer 43

IL-6

Question 44

_______ is produced by TAMs and can activate NF-KB and AP-1 family of TFs in tumor cells, stimulating their proliferation and survival

Answer 44

TNF-alpha

Question 45

The cytokine ____ enhances activity of Th17 cells (helper T cell with strong inflammatory effects) and inhibits activity of T-regs.

Answer 45

IL-23

Question 46

MicroRNAs can serve as positive and negative regulators of EMT. _____ and _____ prevent EMT by inhibiting Zeb-1 and Zeb-2, which are repressors of E-cadherin expression. ______ supports TGF-B dependent EMT.

Answer 46

- miR-200 and miR-205 - miR-21

Question 47

List the metastasis-suppressor genes.

Answer 47

- NME1 - KAI-1/CD82 - KiSS-1 - BrMS-1 - MAPK4

Question 48

In what canine malignancy were MMPs and TIMP-1 found to be expressed at the invasive front of tumors, which were similar findings to the mouse?

Answer 48

histiocytic sarcoma

Question 49

MMPs ____ and _____ were found to correlate with clinicopathologic features in canine oral cancers and _____ and ______ were associated with early-stage tumors.

Answer 49

- MMP7 and MMP2 - TIMP1 and MMP4

Question 50

Which cathepsin was shown to be secreted by osteoclasts which result in degradation of bone matrix? Inhibition of this cathepsin might aid in management of canine OSA-related malignant osteolysis.

Answer 50

Cathepsin K

Question 51

What canine malignancy has been shown to have markedly increased expression of osteopontin?

Answer 51

thyroid carcinoma

Question 52

Degree of ezrin expression in primary tumor of dogs with ______ was shown to predict more aggressive biologic behavior (ie, lung metastasis).

Answer 52

OSA

Question 53

What is osteoprotegerin?

Answer 53

RANKL antagonist

Question 54

In dogs and cats, tumors involving bone and causing pain, often may express ________, which can be a potential target for therapy.

Answer 54

RANKL

Question 55

MMPs can be auto-catalyzed, activated by other MMPs or activated by _______ proteinases. Cell-surface anchored proteases, such as MT-MMPs, are activated by ___________, some of which are also critical for the localization and cell-surface activation of soluble pro-MMPs.

Answer 55

- serine - proprotein convertases

Question 56

List the MMPs involved in tumor angiogenesis.

Answer 56

MMP-1, MMP-2, MMP-9 and MMP-14

Question 57

Increased MMP activity can sometimes be associated with a favorable prpgnpsis, ie, ________ in colon cancer.

Answer 57

MMP-12

Question 58

Increased levels of ______, _____, and _____ (MMP inhibitors) reduce the invasive and metastatic ability of malignant cells. ______ provides increased resistant to metastatic colonization of organs.

Answer 58

- TIMP-1, -2, and -3 - TIMP-1

Question 59

______ and _____ are proteinase inhibitors that are considered broad-spectrum peptidic hydroxamates. What do they treat?

Answer 59

Batimastat (ascites) and Marimastat (variety of tumors).

Question 60

______ is a proteinase inhibitor that is considered a selective collagenase hydroxamate. It is used to treat arthritis.

Answer 60

Trocade

Question 61

_______ is a proteinase inhibitor that is considered a selective gelatinase non-peptidic biphenyl. It is used tot reat small cell lung cancer.

Answer 61

Tanomastat

Question 62

________ is a proteinase inhibitor that is considered a selective gelatinase non-peptidic hydroxamate. It is used to treat NSCLC.

Answer 62

Prinomastat

Question 63

______ is a proteinase inhibitor that is considered a chemically modified tetracycline. It is used to treat Kaposi's sarcoma.

Answer 63

Metastat

Question 64

Which MMPs have been shown to play an important role in canine mammary tumors? The reduction of ____ and ____ may also play a significant step in malignant transformation

Answer 64

- MMP-9, MMP-2, and MT1-MMP - MMP-13 and TIMP-2

Question 65

______ and _____ are expressed in meningiomas of dogs and are considered type IV collagenases.

Answer 65

MMP-2 and MMP-9

Question 66

________ imbalance might contribute to the aggressive biologic behavior of papillary meningiomas in dogs.

Answer 66

MMP-2/TIMP-2

Question 67

Many anticoagulant drugs have been assessed for their ability to inhibit metastasis. There are consistent reports of reduced metastasis in animal systems by treatment with _____, _____, and _____.

Answer 67

heparin, warfarin, and inhibitors of platelet aggregation

Question 68

Use of peptides, blocking the integrin motif RDG, which involved binding of cells to fibronectin, were largely _____.

Answer 68

ineffective

Question 69

________ normalizes the structure of tumor blood vessels and has been found to be effective as an antimetastatic agent in animal models. Improved outcome in patients with _____ when combined with vindesine an radiation and surgery. A possible link to ___ halted further development of the drug.

Answer 69

- Razoxane - STS - Leukemia

Question 70

Discovery of "premetastatic niches" may provide an opportunity for early treatment to prevent the development of metastasis using inhibitors of components of this process, such as ______.

Answer 70

LOX

Question 71

List ways metastasis can be inhibited.

Answer 71

- inhibition of premetastatic niche - inhibition of angiogenesis - MMP inhibitors - anticoagulant drugs - integrin antagonists