title: Tumor associated mesenchymal stem cells protects ovarian cancer cells from hyperthermia through CXCL12.
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.
authors: Stem Cell and Microenvironment Laboratory, Weill Cornell Medical College, Education City, Qatar Foundation, Doha, Qatar.
authors: Raphael
authors: R
authors: Lis
authors: Cyril
authors: C
authors: Touboul
authors: Pejman
authors: P
authors: Mirshahi
authors: Fadoua
authors: F
authors: Ali
authors: Sharon
authors: S
authors: Mathew
authors: Daniel J
authors: DJ
authors: Nolan
authors: Mahtab
authors: M
authors: Maleki
authors: Salma A
authors: SA
authors: Abdalla
authors: Christophe M
authors: CM
authors: Raynaud
authors: Denis
authors: D
authors: Querleu
authors: Eman
authors: E
authors: Al-Azwani
authors: Joel
authors: J
authors: Malek
authors: Massoud
authors: M
authors: Mirshahi
authors: Arash
authors: A
authors: Rafii
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival; D054377:Chemokine CXCL12 / Q000037:antagonists & inhibitors; D018920:Coculture Techniques; D005260:Female; D005434:Flow Cytometry; D017930:Genes, Reporter; D049452:Green Fluorescent Proteins / Q000235:genetics; D006358:Hot Temperature; D006801:Humans; D006979:Hyperthermia, Induced; D059630:Mesenchymal Stem Cells / Q000378:metabolism / Q000473:pathology / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000401:mortality / Q000473:pathology*; D019718:Receptors, CXCR4 / Q000037:antagonists & inhibitors; D015996:Survival Rate
chemical_list: D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D049452:Green Fluorescent Proteins