Limits...
The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian cancer.

Lane D, Matte I, Rancourt C, Piché A - J Ovarian Res (2010)

Bottom Line: The effect of ascites on cisplatin- and paclitaxel-induced cell death was assessed with 4 ascites having inhibitory effect on TRAIL-induced cell death and 2 that do not.Among a cohort of 35 patients with ascites, a threshold of TRAIL IC(50 )with ascites/IC(50 )without ascites > 2 was associated with shorter disease-free interval.The prosurvival activity of ascites against TRAIL is associated with shorter disease-free interval, which may be explained, at least in part, by ascites-induced cisplatin/paclitaxel resistance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.

ABSTRACT

Background: The production of ascites is a common complication of ovarian cancer. Ascites constitute a unique tumor microenvironment that may affect disease progression. In this context, we recently showed that ovarian cancer ascites may protect tumor cells from TRAIL-induced apoptosis. In this study, we sought to determine whether the prosurvival effect of ascites affects disease-free intervals.

Methods: Peritoneal fluids were obtained from 54 women undergoing intra-abdominal surgery for suspected ovarian cancer (44 cancers and 10 benign diseases). The ability of peritoneal fluids to protect from TRAIL was assessed in the ovarian cancer cell line CaOV3, and IC(50 )were determined. The anti-apoptotic activity of 6 ascites against cisplatin, paclitaxel, doxorubicin, etoposide and vinorelbine was also assessed in CaOV3 cells, and the prosurvival activity of two ascites was assessed in 9 primary ovarian cancer cultures.

Results: Among the 54 peritoneal fluids tested, inhibition of TRAIL cytotoxicity was variable. Fluids originating from ovarian cancer were generally more protective than fluids from non-malignant diseases. Most of the 44 ovarian cancer ascites increased TRAIL IC(50 )and this inhibitory effect did not correlate strongly with the protein concentration in these ascites or the levels of serum CA125, a tumor antigen which is used in the clinic as a marker of tumor burden. The effect of ascites on cisplatin- and paclitaxel-induced cell death was assessed with 4 ascites having inhibitory effect on TRAIL-induced cell death and 2 that do not. The four ascites with prosurvival activity against TRAIL had some inhibitory on cisplatin and/or paclitaxel. Two ovarian cancer ascites, OVC346 and OVC509, also inhibited TRAIL cytotoxicity in 9 primary cultures of ovarian tumor and induced Akt activation in three of these primary cultures. Among a cohort of 35 patients with ascites, a threshold of TRAIL IC(50 )with ascites/IC(50 )without ascites > 2 was associated with shorter disease-free interval.

Conclusions: The prosurvival activity of ascites against TRAIL is associated with shorter disease-free interval, which may be explained, at least in part, by ascites-induced cisplatin/paclitaxel resistance. Our findings suggest that ascites may contain prosurvival factors that protect against TRAIL and chemotherapy and consequently affect disease progression.

No MeSH data available.


Related in: MedlinePlus

Effect of ovarian cancer ascites on TRAIL-induced cell death in primary ovarian tumor samples. (A) Primary cultures ovarian tumor cells (samples 346, 327, 318) were pre-incubated for 2 h with OVC509 (10% v/v) and treated with increasing TRAIL concentrations for 48 h. Cell viability was measured by XTT assay. Data are shown as the percent cell viability relative to TRAIL and ascites untreated cells. Results are from three independent experiments done in triplicate and express as mean ± SEM. *, indicates P < 0,001. (b) TRAIL IC50 were determined in the presence of OVC346 or OVC509 ascites and expressed as fold increased relative to IC50 in the absence of ascites for 9 primary cultures of ovarian tumor cells. Cells were isolated either from ascites (A) or from tissues (T). A value of 1 indicates a neutral effect of ascites on TRAIL cytotoxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC2821314&req=5

Figure 4: Effect of ovarian cancer ascites on TRAIL-induced cell death in primary ovarian tumor samples. (A) Primary cultures ovarian tumor cells (samples 346, 327, 318) were pre-incubated for 2 h with OVC509 (10% v/v) and treated with increasing TRAIL concentrations for 48 h. Cell viability was measured by XTT assay. Data are shown as the percent cell viability relative to TRAIL and ascites untreated cells. Results are from three independent experiments done in triplicate and express as mean ± SEM. *, indicates P < 0,001. (b) TRAIL IC50 were determined in the presence of OVC346 or OVC509 ascites and expressed as fold increased relative to IC50 in the absence of ascites for 9 primary cultures of ovarian tumor cells. Cells were isolated either from ascites (A) or from tissues (T). A value of 1 indicates a neutral effect of ascites on TRAIL cytotoxicity.

Mentions: The prosurvival activity of ascites against TRAIL cytotoxicity has been shown in ovarian cancer cell lines [10] but has never been demonstrated in primary ovarian cancer cultures. Cell-free ovarian cancer ascites OVC509 were added to primary cultures of tumor cells isolated from ascites obtained from advanced (stage III) serous ovarian cancer patients. TRAIL cytotoxicity was significantly reduced in the presence of OVC509 ascites in primary cultures of tumor cells (346, 327, 318 cells) tested with P < 0.001 (Fig. 4A). We extended these data by testing OVC346 and OVC509 ascites in 9 primary cultures. The clinicopathologic data of the 9 primary cultures is shown in Additional file 2, Table S2. TRAIL IC50 was determined in the presence or absence of OVC346 and OVC509 ascites in the 9 primary cultures of ovarian tumor cells (Table 2). When expressed as TRAIL IC50 fold increased, OVC346 and OVC509 displayed anti-apoptotic activity, albeit at different degree in all 9 primary cultures of ovarian cancer (Fig. 4B). OVC509 had stronger anti-apoptotic activity compared to OVC346.


The prosurvival activity of ascites against TRAIL is associated with a shorter disease-free interval in patients with ovarian cancer.

Lane D, Matte I, Rancourt C, Piché A - J Ovarian Res (2010)

Effect of ovarian cancer ascites on TRAIL-induced cell death in primary ovarian tumor samples. (A) Primary cultures ovarian tumor cells (samples 346, 327, 318) were pre-incubated for 2 h with OVC509 (10% v/v) and treated with increasing TRAIL concentrations for 48 h. Cell viability was measured by XTT assay. Data are shown as the percent cell viability relative to TRAIL and ascites untreated cells. Results are from three independent experiments done in triplicate and express as mean ± SEM. *, indicates P < 0,001. (b) TRAIL IC50 were determined in the presence of OVC346 or OVC509 ascites and expressed as fold increased relative to IC50 in the absence of ascites for 9 primary cultures of ovarian tumor cells. Cells were isolated either from ascites (A) or from tissues (T). A value of 1 indicates a neutral effect of ascites on TRAIL cytotoxicity.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2821314&req=5

Figure 4: Effect of ovarian cancer ascites on TRAIL-induced cell death in primary ovarian tumor samples. (A) Primary cultures ovarian tumor cells (samples 346, 327, 318) were pre-incubated for 2 h with OVC509 (10% v/v) and treated with increasing TRAIL concentrations for 48 h. Cell viability was measured by XTT assay. Data are shown as the percent cell viability relative to TRAIL and ascites untreated cells. Results are from three independent experiments done in triplicate and express as mean ± SEM. *, indicates P < 0,001. (b) TRAIL IC50 were determined in the presence of OVC346 or OVC509 ascites and expressed as fold increased relative to IC50 in the absence of ascites for 9 primary cultures of ovarian tumor cells. Cells were isolated either from ascites (A) or from tissues (T). A value of 1 indicates a neutral effect of ascites on TRAIL cytotoxicity.
Mentions: The prosurvival activity of ascites against TRAIL cytotoxicity has been shown in ovarian cancer cell lines [10] but has never been demonstrated in primary ovarian cancer cultures. Cell-free ovarian cancer ascites OVC509 were added to primary cultures of tumor cells isolated from ascites obtained from advanced (stage III) serous ovarian cancer patients. TRAIL cytotoxicity was significantly reduced in the presence of OVC509 ascites in primary cultures of tumor cells (346, 327, 318 cells) tested with P < 0.001 (Fig. 4A). We extended these data by testing OVC346 and OVC509 ascites in 9 primary cultures. The clinicopathologic data of the 9 primary cultures is shown in Additional file 2, Table S2. TRAIL IC50 was determined in the presence or absence of OVC346 and OVC509 ascites in the 9 primary cultures of ovarian tumor cells (Table 2). When expressed as TRAIL IC50 fold increased, OVC346 and OVC509 displayed anti-apoptotic activity, albeit at different degree in all 9 primary cultures of ovarian cancer (Fig. 4B). OVC509 had stronger anti-apoptotic activity compared to OVC346.

Bottom Line: The effect of ascites on cisplatin- and paclitaxel-induced cell death was assessed with 4 ascites having inhibitory effect on TRAIL-induced cell death and 2 that do not.Among a cohort of 35 patients with ascites, a threshold of TRAIL IC(50 )with ascites/IC(50 )without ascites > 2 was associated with shorter disease-free interval.The prosurvival activity of ascites against TRAIL is associated with shorter disease-free interval, which may be explained, at least in part, by ascites-induced cisplatin/paclitaxel resistance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Département de Microbiologie et Infectiologie, Faculté de Médecine, Université de Sherbrooke, 3001, 12ième Avenue Nord, Sherbrooke, J1H 5N4, Canada.

ABSTRACT

Background: The production of ascites is a common complication of ovarian cancer. Ascites constitute a unique tumor microenvironment that may affect disease progression. In this context, we recently showed that ovarian cancer ascites may protect tumor cells from TRAIL-induced apoptosis. In this study, we sought to determine whether the prosurvival effect of ascites affects disease-free intervals.

Methods: Peritoneal fluids were obtained from 54 women undergoing intra-abdominal surgery for suspected ovarian cancer (44 cancers and 10 benign diseases). The ability of peritoneal fluids to protect from TRAIL was assessed in the ovarian cancer cell line CaOV3, and IC(50 )were determined. The anti-apoptotic activity of 6 ascites against cisplatin, paclitaxel, doxorubicin, etoposide and vinorelbine was also assessed in CaOV3 cells, and the prosurvival activity of two ascites was assessed in 9 primary ovarian cancer cultures.

Results: Among the 54 peritoneal fluids tested, inhibition of TRAIL cytotoxicity was variable. Fluids originating from ovarian cancer were generally more protective than fluids from non-malignant diseases. Most of the 44 ovarian cancer ascites increased TRAIL IC(50 )and this inhibitory effect did not correlate strongly with the protein concentration in these ascites or the levels of serum CA125, a tumor antigen which is used in the clinic as a marker of tumor burden. The effect of ascites on cisplatin- and paclitaxel-induced cell death was assessed with 4 ascites having inhibitory effect on TRAIL-induced cell death and 2 that do not. The four ascites with prosurvival activity against TRAIL had some inhibitory on cisplatin and/or paclitaxel. Two ovarian cancer ascites, OVC346 and OVC509, also inhibited TRAIL cytotoxicity in 9 primary cultures of ovarian tumor and induced Akt activation in three of these primary cultures. Among a cohort of 35 patients with ascites, a threshold of TRAIL IC(50 )with ascites/IC(50 )without ascites > 2 was associated with shorter disease-free interval.

Conclusions: The prosurvival activity of ascites against TRAIL is associated with shorter disease-free interval, which may be explained, at least in part, by ascites-induced cisplatin/paclitaxel resistance. Our findings suggest that ascites may contain prosurvival factors that protect against TRAIL and chemotherapy and consequently affect disease progression.

No MeSH data available.


Related in: MedlinePlus