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Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours.

Rafii A, Mirshahi P, Poupot M, Faussat AM, Simon A, Ducros E, Mery E, Couderc B, Lis R, Capdet J, Bergalet J, Querleu D, Dagonnet F, Fournié JJ, Marie JP, Pujade-Lauraine E, Favre G, Soria J, Mirshahi M - PLoS ONE (2008)

Bottom Line: Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance.This interaction induced autonomous acquisition of chemoresistance.The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: UMRS 872 INSERM, Université Pierre et Marie Curie-Paris 6 and Université Paris Descartes, Equipe 18, Centre de Recherche des Cordeliers, Paris, France.

ABSTRACT

Background: The microenvironment plays a major role in the onset and progression of metastasis. Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneal cavity where interactions within the microenvironment might lead to chemoresistance. Mesothelial cells are important actors of the peritoneal homeostasis; we determined their role in the acquisition of chemoresistance of ovarian tumours.

Methodology/principal findings: We isolated an original type of stromal cells, referred to as "Hospicells" from ascitis of patients with ovarian carcinosis using limiting dilution. We studied their ability to confer chemoresistance through heterocellular interactions. These stromal cells displayed a new phenotype with positive immunostaining for CD9, CD10, CD29, CD146, CD166 and Multi drug resistance protein. They preferentially interacted with epithelial ovarian cancer cells. This interaction induced chemoresistance to platin and taxans with the implication of multi-drug resistance proteins. This contact enabled EOC cells to capture patches of the Hospicells membrane through oncologic trogocytosis, therefore acquiring their functional P-gp proteins and thus developing chemoresistance. Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance.

Conclusions/significance: This is the first report of trogocytosis occurring between a cancer cell and an original type of stromal cell. This interaction induced autonomous acquisition of chemoresistance. The presence of stromal cells within patient's tumour might be predictive of chemoresistance. The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.

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Chemoresistance induced by Hospicells.A. Induced chemoresistance when Hospicells co-cultured with OVCAR3 cells over-expressing e-GFP are treated with 22.2 µM carboplatin and/or 1.4 µM paclitaxel (* p>0.05). Fibroblasts, HBMEC and OVCAR3 cells were used as controls. B. Same assay using a transwell co-culture system. C. Reversal of chemoresistance by treating the co-culture by 50 µM verapamil. Cell density is expressed as the optical density (OD), means with standard deviations (6 replicates were used per experiments. The experiments were performed 3 times).
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pone-0003894-g004: Chemoresistance induced by Hospicells.A. Induced chemoresistance when Hospicells co-cultured with OVCAR3 cells over-expressing e-GFP are treated with 22.2 µM carboplatin and/or 1.4 µM paclitaxel (* p>0.05). Fibroblasts, HBMEC and OVCAR3 cells were used as controls. B. Same assay using a transwell co-culture system. C. Reversal of chemoresistance by treating the co-culture by 50 µM verapamil. Cell density is expressed as the optical density (OD), means with standard deviations (6 replicates were used per experiments. The experiments were performed 3 times).

Mentions: We were able to demonstrate that co-culture of the two cellular sub-types gave a significant proliferative advantage to the cancer cells. The proliferative advantage was also demonstrated in an in-vivo model of peritoneal carcinosis (Supplementary Figure S1). To investigate their potential role in chemoresistance we conducted a chemoresistance assay. Firstly we demonstrated as displayed in Figure 4A that the co-culture of Hospicells and OVCAR3 cells induced a chemo-resistant profile with differences of 2.2 to 2.5 fold between the co-culture and the eGFP-OVCAR3 cells alone depending the chemotherapeutic agents used, (p<0.05). This effect was Hospicells specific, HBMEC and fibroblasts being unable to confer chemoresistance, and was mediated by direct cell contact as shown by transwell experiments (Figure 4B). We then investigated the role of Multi Drug Resistance (MDR) proteins by conducting a chemoresistance assay in the presence of the selective drug-efflux pump inhibitor, Verapamil [18], [19]. Verapamil abrogated the acquisition of chemoresistance (Figure 4C), thus establishing the involvement of MDR proteins. The effect of Hospicells among ECOA was assessed by treating freshly isolated ECOA form non-previously treated patients with ovarian peritoneal carcinosis. As displayed in Figure 5, when treated by carboplatin or paclitaxel ECOA managed to survive compared to isolated cancer cells.


Oncologic trogocytosis of an original stromal cells induces chemoresistance of ovarian tumours.

Rafii A, Mirshahi P, Poupot M, Faussat AM, Simon A, Ducros E, Mery E, Couderc B, Lis R, Capdet J, Bergalet J, Querleu D, Dagonnet F, Fournié JJ, Marie JP, Pujade-Lauraine E, Favre G, Soria J, Mirshahi M - PLoS ONE (2008)

Chemoresistance induced by Hospicells.A. Induced chemoresistance when Hospicells co-cultured with OVCAR3 cells over-expressing e-GFP are treated with 22.2 µM carboplatin and/or 1.4 µM paclitaxel (* p>0.05). Fibroblasts, HBMEC and OVCAR3 cells were used as controls. B. Same assay using a transwell co-culture system. C. Reversal of chemoresistance by treating the co-culture by 50 µM verapamil. Cell density is expressed as the optical density (OD), means with standard deviations (6 replicates were used per experiments. The experiments were performed 3 times).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2597737&req=5

pone-0003894-g004: Chemoresistance induced by Hospicells.A. Induced chemoresistance when Hospicells co-cultured with OVCAR3 cells over-expressing e-GFP are treated with 22.2 µM carboplatin and/or 1.4 µM paclitaxel (* p>0.05). Fibroblasts, HBMEC and OVCAR3 cells were used as controls. B. Same assay using a transwell co-culture system. C. Reversal of chemoresistance by treating the co-culture by 50 µM verapamil. Cell density is expressed as the optical density (OD), means with standard deviations (6 replicates were used per experiments. The experiments were performed 3 times).
Mentions: We were able to demonstrate that co-culture of the two cellular sub-types gave a significant proliferative advantage to the cancer cells. The proliferative advantage was also demonstrated in an in-vivo model of peritoneal carcinosis (Supplementary Figure S1). To investigate their potential role in chemoresistance we conducted a chemoresistance assay. Firstly we demonstrated as displayed in Figure 4A that the co-culture of Hospicells and OVCAR3 cells induced a chemo-resistant profile with differences of 2.2 to 2.5 fold between the co-culture and the eGFP-OVCAR3 cells alone depending the chemotherapeutic agents used, (p<0.05). This effect was Hospicells specific, HBMEC and fibroblasts being unable to confer chemoresistance, and was mediated by direct cell contact as shown by transwell experiments (Figure 4B). We then investigated the role of Multi Drug Resistance (MDR) proteins by conducting a chemoresistance assay in the presence of the selective drug-efflux pump inhibitor, Verapamil [18], [19]. Verapamil abrogated the acquisition of chemoresistance (Figure 4C), thus establishing the involvement of MDR proteins. The effect of Hospicells among ECOA was assessed by treating freshly isolated ECOA form non-previously treated patients with ovarian peritoneal carcinosis. As displayed in Figure 5, when treated by carboplatin or paclitaxel ECOA managed to survive compared to isolated cancer cells.

Bottom Line: Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance.This interaction induced autonomous acquisition of chemoresistance.The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.

View Article: PubMed Central - PubMed

Affiliation: UMRS 872 INSERM, Université Pierre et Marie Curie-Paris 6 and Université Paris Descartes, Equipe 18, Centre de Recherche des Cordeliers, Paris, France.

ABSTRACT

Background: The microenvironment plays a major role in the onset and progression of metastasis. Epithelial ovarian cancer (EOC) tends to metastasize to the peritoneal cavity where interactions within the microenvironment might lead to chemoresistance. Mesothelial cells are important actors of the peritoneal homeostasis; we determined their role in the acquisition of chemoresistance of ovarian tumours.

Methodology/principal findings: We isolated an original type of stromal cells, referred to as "Hospicells" from ascitis of patients with ovarian carcinosis using limiting dilution. We studied their ability to confer chemoresistance through heterocellular interactions. These stromal cells displayed a new phenotype with positive immunostaining for CD9, CD10, CD29, CD146, CD166 and Multi drug resistance protein. They preferentially interacted with epithelial ovarian cancer cells. This interaction induced chemoresistance to platin and taxans with the implication of multi-drug resistance proteins. This contact enabled EOC cells to capture patches of the Hospicells membrane through oncologic trogocytosis, therefore acquiring their functional P-gp proteins and thus developing chemoresistance. Presence of Hospicells on ovarian cancer tissue micro-array from patients with neo-adjuvant chemotherapy was also significantly associated to chemoresistance.

Conclusions/significance: This is the first report of trogocytosis occurring between a cancer cell and an original type of stromal cell. This interaction induced autonomous acquisition of chemoresistance. The presence of stromal cells within patient's tumour might be predictive of chemoresistance. The specific interaction between cancer cells and stromal cells might be targeted during chemotherapy.

Show MeSH
Related in: MedlinePlus