Bioactive Lipids, LPC and LPA, Are Novel Prometastatic Factors and Their Tissue Levels Increase in Response to Radio/Chemotherapy

Schneider, Gabriela; Sellers, Zachariah Payne; Abdel‐Latif, Ahmed; Morris, Andrew J.; Ratajczak, Mariusz Z.

doi:10.1158/1541-7786.mcr-14-0188

Cited by 38 publications

(57 citation statements)

References 45 publications

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“…We found that dialysis did not affect the chemotactic activity of ascites fluids which suggests that molecules smaller than 3.5 kDa are not involved in this process (Figure 1E). Next we charcoal stripped ascites fluid and removed potential pro-migratory bioactive lipids [6, 8]. Figure 1E shows that charcoal stripping, similar to dialysis did not inhibit pro-migratory activity of ascites fluid, which indicates that bioactive lipids are not responsible for observed pro-migratory response of ovarian cancer cells.…”

Section: Resultsmentioning

confidence: 99%

“…Chemotaxis assays were performed as described [6–8]. In some experiments the cells were pretreated with the inhibitors: ATN161 (100–500 μM, Medkoo Biosciences, Chapel Hill, NC) for 30 min or RGD (1 – 100 μM, ApexBio Technology, Houston, TX) for 60 min at 37°C.…”

Section: Methodsmentioning

confidence: 99%

“…Western blots analysis to assess phosphorylation of MAPKp42/44 and AKT was performed as described [6–8]. …”

Section: Methodsmentioning

confidence: 99%

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Vitronectin in the Ascites of Human Ovarian Carcinoma Acts as a Potent Chemoattractant for Ovarian Carcinoma: Implication for Metastasis by Cancer Stem Cells

Schneider

Suszyńska

Kakar

et al. 2016

J Cancer Stem Cell Res

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Vitronectin has been identified mainly as an adhesion protein that signals through uPAR and selected integrin receptors. In addition to its pro-adhesive properties, we identified recently vitronectin as a main chemoattractant present in diluted plasma/serum that directly stimulates migration of cancer cells. We also found that this pro-migratory activity of vitronectin can be quenched by fibrinogen. Based on this we hypothesized that this may explain preference of cancer cell to metastasize to fibrinogen-low microenvironments such as lymphatics or peritoneal cavity. Based on this, we decided to investigate a role of vitronectin in metastasis of ovarian cancer cells to peritoneal cavity. We tested migratory responsiveness of three human ovarian cancer cell lines to ascites isolated from ovarian cancer patients and characterize possible molecules involved in migration of ovarian cancer cells. The ascites samples were exposed to heat inactivation, proteinase K digested, dialyzed and charcoal stripped. We also performed cut-off filtration analysis and by employing ELISA assays to measure concentration of vitronectin in ascites fluid samples. Finally, we employed shRNA against uPAR and small molecular inhibitors of integrin receptors to assess their involvement in biological effects of vitronectin. From our studies, we found that the similarly to diluted plasma, vitronectin in absence of fibrinogen is a main chemotactic/chemokinetic protein present in ascites fluid. We also found that these pro-migratory properties of vitronectin can be quenched by addition of fibrinogen. Our studies also indicate that both uPAR and integrin receptors on ovarian cancer cells regulate migration of these cells to vitronectin gradient. In summary, we identified free soluble vitronectin as a potent direct chemoattractant for ovarian cancer cells and that its activity is suppressed after binding to fibrinogen. Since in ascites fluids vitronectin is present in free form because of a lack or low level of fibrinogen, this could explain preferences of ovarian cancer stem cells to metastasize within peritoneum. We propose that inhibitors which could sequester soluble vitronectin in similar fashion as fibrinogen, could be employed as a novel anti-metastatic drugs.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Vitronectin in the Ascites of Human Ovarian Carcinoma Acts as a Potent Chemoattractant for Ovarian Carcinoma: Implication for Metastasis by Cancer Stem Cells

Schneider

Suszyńska

Kakar

et al. 2016

J Cancer Stem Cell Res

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“…These factors may promote metastasis by chemoattracting cancer cells that survived the initial treatment [9–11, 30]. Of note, we have already observed that the concentration of vitronectin increases in tissues irradiated or exposed to chemotherapeutic agents (manuscript in preparation).…”

Section: Discussionmentioning

confidence: 99%

Evidence that vitronectin is a potent migration-enhancing factor for cancer cells chaperoned by fibrinogen: a novel view of the metastasis of cancer cells to low-fibrinogen lymphatics and body cavities

et al. 2016

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Diluted (1%) plasma induces migration of malignant cell lines much more strongly than potent pro-metastatic factors. To characterize the factor(s) present in diluted plasma responsible for this phenomenon we performed i) heat inactivation, ii) dialysis, iii) proteinase K treatment, and iv) molecular size filtration studies. We found that this remarkable pro-migratory activity of diluted normal plasma is associated with a ~50–100-kD protein that interacts with GαI protein-coupled receptors and activates p42/44 MAPK and AKT signaling in target cells. Since this pro-migratory activity of 1% plasma decreases at higher plasma concentrations (> 20%), but is retained in serum, we hypothesized that fibrinogen may be involved as a chaperone of the protein(s). To identify the pro-migratory protein(s) present in diluted plasma and fibrinogen-depleted serum, we performed gel filtration and hydrophobic interaction chromatography followed by mass spectrometry analysis. We identified several putative protein candidates that were further tested in in vitro experiments. We found that this pro-migratory factor chaperoned by fibrinogen is vitronectin, which activates uPAR, and that this effect can be inhibited by fibrinogen. These results provide a novel mechanism for the metastasis of cancer cells to lymphatics and body cavities, in which the concentration of fibrinogen is low, and thus suggests that free vitronectin stimulates migration of tumor cells.

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“…Chemotaxis assays were performed in a modified Boyden’s chamber with 8-μm pore polycarbonate membrane inserts (Costar Transwell; Corning Costar, Lowell, MA, USA) as described previously [10]. In brief, freshly sorted cells (CD24 − CD44 + , CD24 + CD44 − , and CD24 − CD44 − ) from the A2780 cell line were seeded into the upper chamber of an insert at a density of 2 × 10 4 in 110 μl.…”

Section: Methodsmentioning

confidence: 99%

An emerging question about putative cancer stem cells in established cell lines—are they true stem cells or a fluctuating cell phenotype?

Gunjal¹,

Pędziwiatr²,

Abdelbaset‐Ismail³

et al. 2015

J Cancer Stem Cell Res

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It has been proposed that established cell lines contain populations of cancer stem cells (CSCs), which are responsible for expansion of these cell lines and their metastatic potential. To address this issue better, we employed a human ovarian cancer cell line, A2780, and sorted cells according to the postulated highly mestatatic cancer stem cell phenotype, CD24+CD44−, and the less-metastatic CD24−CD44+ and CD24−CD44− phenotypes. These cells were employed in chemotaxis assays in vitro to migrate in response to conditioned media harvested from bone marrow or liver cells damaged by irradiation and in in vivo assays to grow tumors after injection into immunodeficient mice. We also sorted single cells expressing all three phenotypes by FACS and expanded them to grow clones. We found that the CD24+CD44− cells are a highly migratory population compared with CD24−CD44+ and CD24−CD44− cells and were seeded in higher numbers in murine bone marrow and liver after intravenous injection. Most importantly, we observed that singly sorted cells efficiently expanded ex vivo into cell populations that represented all phenotypes of the parental cell line. Thus, our data indicate that cells expressing a certain set of markers, e.g., CD24, have at any given moment a higher potential to migrate and metastasize. However, cells that are CD24-negative, if expanded from a singly sorted cell, may give rise to cells containing all of the markers, including CD24. Based on this finding, we propose that the CSC phenotype in cell lines fluctuates with cell expansion.

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Bioactive Lipids, LPC and LPA, Are Novel Prometastatic Factors and Their Tissue Levels Increase in Response to Radio/Chemotherapy

Cited by 38 publications

References 45 publications

Vitronectin in the Ascites of Human Ovarian Carcinoma Acts as a Potent Chemoattractant for Ovarian Carcinoma: Implication for Metastasis by Cancer Stem Cells

Vitronectin in the Ascites of Human Ovarian Carcinoma Acts as a Potent Chemoattractant for Ovarian Carcinoma: Implication for Metastasis by Cancer Stem Cells

Evidence that vitronectin is a potent migration-enhancing factor for cancer cells chaperoned by fibrinogen: a novel view of the metastasis of cancer cells to low-fibrinogen lymphatics and body cavities

An emerging question about putative cancer stem cells in established cell lines—are they true stem cells or a fluctuating cell phenotype?

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