Surgical peritoneal stress creates a pro-metastatic niche promoting resistance to apoptosis via IL-8 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 11 Medical and Health Sciences 1103 Clinical Sciences

Jennifer Pasquier, Fabien Vidal, Jessica Hoarau, Claire Bonneau, Emile Daraï, Cyril Touboul, Arash Rafii Tabrizi

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Abstract

Background: The mainstay of treatment of advanced ovarian cancer (AOC) involves chemotherapy, and debulking surgery. However, despite optimal surgical procedure and adjuvant chemotherapy, 60% of patients with AOC will relapse within 5 years. Most recurrences occur in the peritoneal cavity, suggesting the existence of occult sanctuaries where ovarian cancer cells (OCC) are protected. In murine models, surgical stress favors tumor growth; however, it has never been established that surgery may affect OCC sensitivity to subsequent chemotherapy. In this study, we investigated how the surgical stress could affect the chemosensitivity of OCC. Methods: To avoid bias due to tumor burden in peritoneal cavity and duration of surgery, we used peritoneal biopsies from patients without a malignancy at precise time points. During laparotomies, peritoneal biopsies at the incision site were performed at the time of incision (H0 sample) and 1 h after initiation of surgery (H1 sample). We evaluated the chemoresistance to Taxol (0-20 μM) induced by H0 or H1 incubation (24 h) in two ovarian cancer cell lines OVCAR3 and SKOV3 and a primary cancer cell lines derived in our laboratory. Results: Our results indicate that stressed peritoneum overexpressed cytokines, resulting in OCC increased resistance to therapy. Among these cytokines, IL8 was responsible for the resistance to apoptosis through the AKT pathway activation. Chemoresistance in OCC persists through the establishment of an autocrine IL8 loop. Finally, in a cohort of 32 patients, we showed an impact of IL8 tumoral overexpression on chemosensitivity and survival outcomes with a significant association to earlier recurrence. Conclusions: Our study demonstrated that precision surgery where targeted treatment would be used in combination with surgery is essential to obtain better tumor control.

Original languageEnglish
Article number271
JournalJournal of Translational Medicine
Volume16
Issue number1
DOIs
Publication statusPublished - 3 Oct 2018

Fingerprint

Interleukin-11
Oncology
Interleukin-8
Ovarian Neoplasms
Surgery
Carcinogenesis
Health
Apoptosis
Chemotherapy
Tumors
Biopsy
Cells
Peritoneal Cavity
Recurrence
Cytokines
Neoplasms
Paclitaxel
Anatomic Models
Drug Therapy
Cell Line

Keywords

  • Chemoresistance
  • IL8
  • Ovarian cancer
  • Surgery
  • Tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

@article{530064b171014d06a33b0a537526d5b3,
title = "Surgical peritoneal stress creates a pro-metastatic niche promoting resistance to apoptosis via IL-8 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 11 Medical and Health Sciences 1103 Clinical Sciences",
abstract = "Background: The mainstay of treatment of advanced ovarian cancer (AOC) involves chemotherapy, and debulking surgery. However, despite optimal surgical procedure and adjuvant chemotherapy, 60{\%} of patients with AOC will relapse within 5 years. Most recurrences occur in the peritoneal cavity, suggesting the existence of occult sanctuaries where ovarian cancer cells (OCC) are protected. In murine models, surgical stress favors tumor growth; however, it has never been established that surgery may affect OCC sensitivity to subsequent chemotherapy. In this study, we investigated how the surgical stress could affect the chemosensitivity of OCC. Methods: To avoid bias due to tumor burden in peritoneal cavity and duration of surgery, we used peritoneal biopsies from patients without a malignancy at precise time points. During laparotomies, peritoneal biopsies at the incision site were performed at the time of incision (H0 sample) and 1 h after initiation of surgery (H1 sample). We evaluated the chemoresistance to Taxol (0-20 μM) induced by H0 or H1 incubation (24 h) in two ovarian cancer cell lines OVCAR3 and SKOV3 and a primary cancer cell lines derived in our laboratory. Results: Our results indicate that stressed peritoneum overexpressed cytokines, resulting in OCC increased resistance to therapy. Among these cytokines, IL8 was responsible for the resistance to apoptosis through the AKT pathway activation. Chemoresistance in OCC persists through the establishment of an autocrine IL8 loop. Finally, in a cohort of 32 patients, we showed an impact of IL8 tumoral overexpression on chemosensitivity and survival outcomes with a significant association to earlier recurrence. Conclusions: Our study demonstrated that precision surgery where targeted treatment would be used in combination with surgery is essential to obtain better tumor control.",
keywords = "Chemoresistance, IL8, Ovarian cancer, Surgery, Tumor microenvironment",
author = "Jennifer Pasquier and Fabien Vidal and Jessica Hoarau and Claire Bonneau and Emile Dara{\"i} and Cyril Touboul and Tabrizi, {Arash Rafii}",
year = "2018",
month = "10",
day = "3",
doi = "10.1186/s12967-018-1643-z",
language = "English",
volume = "16",
journal = "Journal of Translational Medicine",
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T1 - Surgical peritoneal stress creates a pro-metastatic niche promoting resistance to apoptosis via IL-8 11 Medical and Health Sciences 1112 Oncology and Carcinogenesis 11 Medical and Health Sciences 1103 Clinical Sciences

AU - Pasquier, Jennifer

AU - Vidal, Fabien

AU - Hoarau, Jessica

AU - Bonneau, Claire

AU - Daraï, Emile

AU - Touboul, Cyril

AU - Tabrizi, Arash Rafii

PY - 2018/10/3

Y1 - 2018/10/3

N2 - Background: The mainstay of treatment of advanced ovarian cancer (AOC) involves chemotherapy, and debulking surgery. However, despite optimal surgical procedure and adjuvant chemotherapy, 60% of patients with AOC will relapse within 5 years. Most recurrences occur in the peritoneal cavity, suggesting the existence of occult sanctuaries where ovarian cancer cells (OCC) are protected. In murine models, surgical stress favors tumor growth; however, it has never been established that surgery may affect OCC sensitivity to subsequent chemotherapy. In this study, we investigated how the surgical stress could affect the chemosensitivity of OCC. Methods: To avoid bias due to tumor burden in peritoneal cavity and duration of surgery, we used peritoneal biopsies from patients without a malignancy at precise time points. During laparotomies, peritoneal biopsies at the incision site were performed at the time of incision (H0 sample) and 1 h after initiation of surgery (H1 sample). We evaluated the chemoresistance to Taxol (0-20 μM) induced by H0 or H1 incubation (24 h) in two ovarian cancer cell lines OVCAR3 and SKOV3 and a primary cancer cell lines derived in our laboratory. Results: Our results indicate that stressed peritoneum overexpressed cytokines, resulting in OCC increased resistance to therapy. Among these cytokines, IL8 was responsible for the resistance to apoptosis through the AKT pathway activation. Chemoresistance in OCC persists through the establishment of an autocrine IL8 loop. Finally, in a cohort of 32 patients, we showed an impact of IL8 tumoral overexpression on chemosensitivity and survival outcomes with a significant association to earlier recurrence. Conclusions: Our study demonstrated that precision surgery where targeted treatment would be used in combination with surgery is essential to obtain better tumor control.

AB - Background: The mainstay of treatment of advanced ovarian cancer (AOC) involves chemotherapy, and debulking surgery. However, despite optimal surgical procedure and adjuvant chemotherapy, 60% of patients with AOC will relapse within 5 years. Most recurrences occur in the peritoneal cavity, suggesting the existence of occult sanctuaries where ovarian cancer cells (OCC) are protected. In murine models, surgical stress favors tumor growth; however, it has never been established that surgery may affect OCC sensitivity to subsequent chemotherapy. In this study, we investigated how the surgical stress could affect the chemosensitivity of OCC. Methods: To avoid bias due to tumor burden in peritoneal cavity and duration of surgery, we used peritoneal biopsies from patients without a malignancy at precise time points. During laparotomies, peritoneal biopsies at the incision site were performed at the time of incision (H0 sample) and 1 h after initiation of surgery (H1 sample). We evaluated the chemoresistance to Taxol (0-20 μM) induced by H0 or H1 incubation (24 h) in two ovarian cancer cell lines OVCAR3 and SKOV3 and a primary cancer cell lines derived in our laboratory. Results: Our results indicate that stressed peritoneum overexpressed cytokines, resulting in OCC increased resistance to therapy. Among these cytokines, IL8 was responsible for the resistance to apoptosis through the AKT pathway activation. Chemoresistance in OCC persists through the establishment of an autocrine IL8 loop. Finally, in a cohort of 32 patients, we showed an impact of IL8 tumoral overexpression on chemosensitivity and survival outcomes with a significant association to earlier recurrence. Conclusions: Our study demonstrated that precision surgery where targeted treatment would be used in combination with surgery is essential to obtain better tumor control.

KW - Chemoresistance

KW - IL8

KW - Ovarian cancer

KW - Surgery

KW - Tumor microenvironment

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U2 - 10.1186/s12967-018-1643-z

DO - 10.1186/s12967-018-1643-z

M3 - Article

VL - 16

JO - Journal of Translational Medicine

JF - Journal of Translational Medicine

SN - 1479-5876

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