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Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12

Author(s): Lis, R (Lis, Raphael); Touboul, C (Touboul, Cyril); Mirshahi, P (Mirshahi, Pejman); Ali, F (Ali, Fadoua); Mathew, S (Mathew, Sharon); Nolan, DJ (Nolan, Daniel J.); Maleki, M (Maleki, Mahtab); Abdalla, SA (Abdalla, Salma A.); Raynaud, CM (Raynaud, Christophe M.); Querleu, D (Querleu, Denis); Al-Azwani, E (Al-Azwani, Eman); Malek, J (Malek, Joel); Mirshahi, M (Mirshahi, Massoud); Rafii, A (Rafii, Arash) Source: INTERNATIONAL JOURNAL OF CANCER, 128 (3): 715-725 FEB 1 2011

Abstract: Hyperthermic intraperitoneal chemotherapy (HIPEC) has shown promise in treatment of ovarian carcinosis. Despite its efficiency for the treatment of peritoneal carcinosis from digestive tract neoplasia, it has failed to demonstrate significant benefit in ovarian cancers. It is therefore essential to understand the mechanism underlying resistance to HIPEC in ovarian cancers. Mesenchymal stem cells (MSC) play an important role in the development of ovarian cancer metastasis and resistance to treatments. A recent study suggests that MSCs may be cytotoxic for cancer cells upon heat shock. In contrast, we describe the protective role of MSC against hyperthermia. Using cytokine arrays we determined that the tumor associated MSC (TAMC) secrete pro-tumoral cytokines. We studied the effect of hyperthermia in co-culture setting of TAMC or BM-MCS associated with ovarian cancer cell lines (SKOV3 and CaOV3) with polyvariate flow cytometry. We demonstrate that hyperthermia does not challenge survival of TAMC or bone marrow derived MSC (BM-MSC). Both TAMC and BM-MSC displayed strong protective effect inducing thermotolerance in ovarian cancer cells (OCC). Transwell experiments demonstrated the role of secreted factors. We showed that CXCL12 was inducing thermotolerance and that inhibition of CXCL12/CXCR4 interaction restored cytotoxicity of hyperthermia in co-culture experiments. Contrary to the previous published study we demonstrated that TAMC and BM-MSC co-cultured with OCC induced thermotolerance in a CXCL12 dependant manner. Targeting the interaction between stromal and cancer cells through CXCL12 inhibition might restore hyperthermia sensitivity in ovarian cancers, and thus improve HIPEC efficiency.

Author(s):  Lis, R (Lis, Raphael); Touboul, C (Touboul, Cyril); Mirshahi, P (Mirshahi, Pejman); Ali, F (Ali, Fadoua); Mathew, S (Mathew, Sharon); Nolan, DJ (Nolan, Daniel J.); Maleki, M (Maleki, Mahtab); Abdalla, SA (Abdalla, Salma A.); Raynaud, CM (Raynaud, Christophe M.); Querleu, D (Querleu, Denis); Al-Azwani, E (Al-Azwani, Eman); Malek, J (Malek, Joel); Mirshahi, M (Mirshahi, Massoud); Rafii, A (Rafii, Arash) 
Source:  INTERNATIONAL JOURNAL OF CANCER, 128 (3): 715-725 FEB 1 2011 
Language:  English 
Document Type:  Article 
Author Keywords:  mesenchymal stem cells; hyperthermia; ovarian cancer resistance; CXCL12 
KeyWords Plus:  INTRAPERITONEAL CHEMOTHERAPY; LYSOPHOSPHATIDIC ACID; STROMAL CELLS; PERITONEAL; CARCINOMA; MANAGEMENT; CYTOREDUCTION; METASTASIS; PACLITAXEL; CISPLATIN 
Addresses:  [Rafii, Arash] Weill Cornell Med Coll Qatar, Qatar Fdn, Stem Cell & Microenvironm Lab, Dept Genet Med & Obstet & Gynecol, Doha, Qatar; [Lis, Raphael; Touboul, Cyril; Mirshahi, Pejman; Mirshahi, Massoud] Univ Paris 06, INSERM, UMRS 872, F-75270 Paris 06, France; [Lis, Raphael; Touboul, Cyril; Mirshahi, Pejman; Mirshahi, Massoud] Univ Paris 05, Equipe 18, Ctr Rech Cordeliers, F-75270 Paris, France; [Nolan, Daniel J.] Weill Cornell Med Coll, Dept Med Genet, Howard Hughes Med Inst, New York, NY USA; [Nolan, Daniel J.] Weill Cornell Med Coll, Ansary Stem Cell Inst, New York, NY USA; [Querleu, Denis] Inst Claudius Regaud, Dept Surg Oncol, F-31052 Toulouse, France; [Querleu, Denis] McGill Univ, Dept Gynecol Oncol, Montreal, PQ, Canada 
Reprint Address:  Rafii, A, Weill Cornell Med Coll Qatar, Qatar Fdn, Stem Cell & Microenvironm Lab, Dept Genet Med & Obstet & Gynecol, Doha, Qatar. 
Funding Agency:  Qatar-Foundation NPRP; Grant number: 08-663-3-140; Grant sponsor: Qatar foundation UREP; Grant number: 07-170-3-031; Grant sponsor: Qatar Foundation, Qatar Technology Transfer
Publisher:  JOHN WILEY & SONS INC 
Publisher Address:  111 RIVER ST, HOBOKEN, NJ 07030 USA 
ISSN:  0020-7136 
29-char Source Abbrev.:  INT J CANCER
ISO Source Abbrev.:  Int. J. Cancer 
Subject Category:  Oncology 
ISI Document Delivery No.:  693ZN 
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