Progression and Metastasis Flashcards
How does receptor activator of nuclear factor-κβ ligand (RANKL) influence tumor progression and metastasis?
a. Promotes tissue extravasation through upregulation of MMPs.
b. Signals for extracellular matrix degradation and intravasation.
c. Creates tumor cell dormancy in metastatic sites, leading to immune system evasion.
d. Recruits nonneoplastic cells to create a suitable tumor microenvironment.
e. Induces osteoclast formation, bone resorption, and bone metastasis.
Answer: e
Tumor cells in bone stimulate osteoblasts release RANKL, which causes myeloid progenitor cells to differentiate into osteoclasts. Osteoclasts then digest bone and create space for establishment of metastasis. This process is normally inhibited by osteoprotegerin (OPG); tumor cells also serve to suppress production of this compound.
A natural compound is being tested for anti-cancer properties. It is found to inhibit tumor cells’ ability to sense environmental changes by preventing interaction of the actin network cytoskeleton with the cell membrane. Which of the following may be theoretically inhibited by this compound?
a. COX-2
b. LOX
c. Ezrin
d. Cathepsin B
e. TIMP-1
Answer: c
Ezrin is one of the ERM proteins (ezrin, radixin, moesin) that links the actin network with the cell membrane. It is overexpressed in a number of cancers, including osteosarcoma, where it is linked with a poor prognosis due to acquisition of metastatic disease.
Epithelial-to-mesenchymal transition (EMT) is due to which of the following alterations?
a. Loss of E-cadherin
b. Gain of desmoplakin
c. Loss of TWIST
d. Gain of β-SMA
e. Loss of Snail and Slug
Answer: a
During EMT, epithelial cells lose expression of cell surface and adhesion proteins (E-cadherin, cytokeratin, ZO-1, laminin). They gain mesenchyma cell surface proteins (N-cadherin, vimentin, fibronectin, alpha-SMA). Certain transcription factors (TWIST, Snail, Slug) serve to repress E-cadherin expression and facilitate EMT. Other inducers of EMT include TFG-β, HGF, and hypoxia (through upregulation of TWIST, Snail and Slug).
The major enzymes responsible for degradation of ECM proteins are:
a. cathepsins b. plasminogen activators c. metalloproteinases d. proteinase inhibitors e. cathepsin inhibitors
Answer: C
Tumor associated macrophages are associated with upregulation of which of the following interleukins that upregulates the Th17, or T-helper cell:
a. IL-1 b. IL-23 c. IL-3 d. IL-5 e. IL-6
Answer: B
ADAMs (a disintegrin and metalloproteinase) molecules are critical for which of the following receptor pathways:
a. NOTCH and EGFR b. EGFR and TIMP expression c. NOTCH and Bcl-2 d. EGFR and Fas e. NOTCH and Caspase 8
Answer: A
Which of the following is true regarding CD44?
a. CD44 binds to the glycoprotein osteopontin, and is associated with tumor invasion and metastasis
b. CD44 is a leukocyte marker whose expression in lymphoma patients is associated with a 2 month decrease in MST
c. Calcium binding to CD44 induces phosphorylation of beta-catenin and upregulation of c-Myc and cyclin D1
d. CD44 typically binds its ligand CXCL12; blocking of this binding impairs development of metastasis in breast cancer cell lines
Answer: a
(b) is made up. (c) is mostly made up but is based on calcium’s interaction with cadherin. (d) is true if you substitute CXCR4 for CD44.
Detection of EpCAM (epithelial cell adhesion molecule) expression on a cell suggests:
a. That cell will stain positive for vimentin despite its epithelial origin
b. That cell has undergone mesenchymal to epithelial transition (MET)
c. If found outside solid tissue, that cell is likely to be a circulating tumor cell
d. That cell if grown in culture has not yet undergone contact-mediated growth inhibition
Answer: c
EpCAM is the most common surface protein used for detection of CTCs. The distractors are absolutely made up.
Which of the following is associated with metastatic progression?
a. Upregulation of NME-1
b. Increased expression if KAI-1
c. Decreased activity of MKK4
d. Loss of CD82
Answer: d
NME-1 and KAI-1 are both involved in metastasis suppression (p. 237). MKK4 increases the likelihood that a tumor can initiate metastatic growth.
Which of the following drugs targets RANKL?
a. Lokivetmab b. Cetuximab c. Panitumumab d. Denosumab
Answer: d
Cetuximab and panitumumab target EGFR. Lokivetmab was found in Wikipedia as a veterinary mab, but couldn’t find any info on it when I googled it.
What is the origin of cancer-associated fibroblasts?
a. Pre-existing fibroblasts within or immediately adjacent to the tumor b. Bone marrow c. Local lymph node d. The tumor
Answer: b
CAFs and pericytes can contribute to cancer promotion via delivery of GF (HGF, FGF), survival signals (IGFs) that counter death signals and activate oncogenes, and provide ECM components for interaction with integrins. Also overexpress MMP, chemokines, and angiogenic factors → proinflammatory and proangiogenic environment.
Which of the following have been shown to correlate with tumor hypoxia?
i. Upregulation of stromal cell derived factor-1 (SDF-1) (CXCL12) ii. Down regulation of TWIST iii. Decreased osteopontin iv. Upregulation of E-cadherin v. Increased transcription of Met a. i, ii, v b. ii, iii, iv c. i, v d. iii, iv, v
Answer: c.
TWIST, Snail 1/2, uPA, uPAR, MMP-2, MMP-9, MET, SDF-1/CXCR4 signaling complex, lysyl oxidase (LOX), and osteopontin, HIF-1, and VEGFA have been shown to be upregulated with tumor hypoxia. Loss of E-cadherin and downregulation of TIMPs has also been observed.