T&H10 Tumor progression and metastasis Flashcards
What is the rate limiting step in tumor progression and metastasis?
breakdown of ECM integrity
Increased _____- mediated activity brings about remodeling of the ECM and basement membrane and influences cell adhesion by cadherins.
MMP
Loss of ____ can promote EMT in cells.
E-cadherin
What are the four major classes of proteinases? List examples of each that have been associated with malignancy and list their inhibitors.
- MMPs
- Example: ADAMS
- Inhibitors: TIMPs - Serine proteases
- Example: plasminogen activators (uPA and tPA) and kallikreins
- Inhibitors: PAIs - Cysteine proteinases
- Example: Cathepsins B, L, and H
- Inhibitors: kinogens, cystatins, stefins - Aspartic proteinases
- Example: Cathepsins D
- No known inhibitor
Tumor cells break through a number of tissue barriers during invasion and metastasis via processes involving ______________.
proteolytic breakdown of the ECM
________ 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.
- ADAMs family of MMPs
- NOTCH and EGFR
_____ are a type of serine proteinase that are best known for being a biomarker for prostate cancer progression (PSA).
Kallikreins
_______ are types of serine proteinases that act on plasminogen to release plasmin.
urokinase type and tissue type plasminogen activators (uPA and tPA)
Plasminogen and plasmin activity is localized to the cell surface by __________, which associates with _____ and can bind to vitronectin in the ECM.
- uPA receptor (uPAR)
- Integrins
Increased uPA expression has been correlated with metastasis in a number of cancers, including ______________.
HER2+ breast cancer
Cathepsins, particularly ___, ___, and ___ have been associated with tumor progression.
B, H, and L
_____ make up a group of transmembrane receptors for proteins of the ECM (ie, fibronectin, laminin, vitronectin, collagens)
integrins
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.
- Beta
- actin cytoskeleton
- focal adhesion plaques (FAPs)
________ interaction plays a role in ECM signaling in primary tumor cells when they first migrate to other organs and thus promote metastasis.
a3B1-FAK
______ are intercellular adhesion molecules important for assembling adhesion junctions and desmosomes.
cadherins
______ are cellular proteins that link cadherins to actin skeleton and to signal transduction components.
catenins
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.
- axin and glycogen synthase kinase (GSK) - 3B
- GSK-3B
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 _____.
c-myc and cyclin D1
Mutations in ___ lead to truncated forms and are unable to bind to B-catenin, which results in reduced degradation.
APC
Degradation of B-catenin can be disrupted if ______ is blocked by activation of the WNT pathway.
GSK-3B
____ 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.
CD44
_____ 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.
CD44
________, a secreted glycoprotein implicated in invasion and metastasis, binds to CD44 and may play a role in malignancy-promoting potential.
osteopontin
______ is a metastasis associated gene that is related to prognosis in a number of cancers. It connects actin skeleton to cell membrane.
ezrin
Tumor cells in hypoxic regions can express ______ to initiate angiogenesis process to compensate for lower nutrient and oxygen supplies.
HIFs
_____ are molecules used by leukocytes to home specific organs and may play a role in organ specificity for metastasis.
chemokines
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).
CXCL12, CCL21
The most common cell-surface protein for circulating tumor cell detection is ____.
EpCAM
What growth factors can induce vascular remodeling and facilitate intravasation?
VEGF and FGF
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 _____.
HGF, autotoxin, or autocrine motility factor
Tumor cells sometimes travel with ____ in the bloodstream to evade immune surveillance.
platelets
What is a reason why so many mets are detected in lungs or liver?
Most tumor cells arrest in first capillary bed they encounter (first-pass bed)
Extravasation involves a variety of proteases with ____ playing a major role.
MMPs
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,
- PTHrP, IL-6, and TNFa
- receptor activator of nuclear factor -kB ligand (RANKL)
_______ was shown to reduce macrometastasis but was ineffective against dormant tumor cells.
Doxorubicin
A number of factors, like _____ and ____, have been implicated in reactivating dormant tumor cells.
VEGF and Id1
_______ is the dominant protease mobilized for cancer cell trafficking through 3D interstitial ECM barriers.
MT1-MMP
MMPs can cleave _____, which promotes bone mets.
RANKL
MMPs play multiple roles in tumor progression and metastasis, including ______, __________, _____________, and _______.
angiogenesis, inflammation regulation, tissue extravasation and intravasation, and creating a metastatic niche.
_____ is a critical activator for cancer associated fibroblasts.
TGF-B
The inflammatory states of tumor associated macrophages are controlled by the transcription factor, ______, which in turn is activated through _____ receptors.
- NF-KB
- toll-like receptors
Tumor associated macrophages exert most of their inflammatory effects via cytokines, such as ___.
IL-6
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.
IL-6
_______ is produced by TAMs and can activate NF-KB and AP-1 family of TFs in tumor cells, stimulating their proliferation and survival
TNF-alpha
The cytokine ____ enhances activity of Th17 cells (helper T cell with strong inflammatory effects) and inhibits activity of T-regs.
IL-23
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.
- miR-200 and miR-205
- miR-21
List the metastasis-suppressor genes.
- NME1
- KAI-1/CD82
- KiSS-1
- BrMS-1
- MAPK4
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?
histiocytic sarcoma
MMPs ____ and _____ were found to correlate with clinicopathologic features in canine oral cancers and _____ and ______ were associated with early-stage tumors.
- MMP7 and MMP2
- TIMP1 and MMP4
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.
Cathepsin K
What canine malignancy has been shown to have markedly increased expression of osteopontin?
thyroid carcinoma
Degree of ezrin expression in primary tumor of dogs with ______ was shown to predict more aggressive biologic behavior (ie, lung metastasis).
OSA
What is osteoprotegerin?
RANKL antagonist
In dogs and cats, tumors involving bone and causing pain, often may express ________, which can be a potential target for therapy.
RANKL
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.
- serine
- proprotein convertases
List the MMPs involved in tumor angiogenesis.
MMP-1, MMP-2, MMP-9 and MMP-14
Increased MMP activity can sometimes be associated with a favorable prpgnpsis, ie, ________ in colon cancer.
MMP-12
Increased levels of ______, _____, and _____ (MMP inhibitors) reduce the invasive and metastatic ability of malignant cells. ______ provides increased resistant to metastatic colonization of organs.
- TIMP-1, -2, and -3
- TIMP-1
______ and _____ are proteinase inhibitors that are considered broad-spectrum peptidic hydroxamates. What do they treat?
Batimastat (ascites) and Marimastat (variety of tumors).
______ is a proteinase inhibitor that is considered a selective collagenase hydroxamate. It is used to treat arthritis.
Trocade
_______ is a proteinase inhibitor that is considered a selective gelatinase non-peptidic biphenyl. It is used tot reat small cell lung cancer.
Tanomastat
________ is a proteinase inhibitor that is considered a selective gelatinase non-peptidic hydroxamate. It is used to treat NSCLC.
Prinomastat
______ is a proteinase inhibitor that is considered a chemically modified tetracycline. It is used to treat Kaposi’s sarcoma.
Metastat
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
- MMP-9, MMP-2, and MT1-MMP
- MMP-13 and TIMP-2
______ and _____ are expressed in meningiomas of dogs and are considered type IV collagenases.
MMP-2 and MMP-9
________ imbalance might contribute to the aggressive biologic behavior of papillary meningiomas in dogs.
MMP-2/TIMP-2
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 _____.
heparin, warfarin, and inhibitors of platelet aggregation
Use of peptides, blocking the integrin motif RDG, which involved binding of cells to fibronectin, were largely _____.
ineffective
________ 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.
- Razoxane
- STS
- Leukemia
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 ______.
LOX
List ways metastasis can be inhibited.
- inhibition of premetastatic niche
- inhibition of angiogenesis
- MMP inhibitors
- anticoagulant drugs
- integrin antagonists
