WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

Ricciardelli, Carmela; Lokman, Noor A.; Ween, Miranda P.; Oehler, Martin K.

doi:10.1530/erc-16-0320

Cited by 23 publications

(21 citation statements)

References 127 publications

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“…11,12 It is also known that Akt signaling pathway is associated with platinum resistance in OvCa cells. [33][34][35][36] Moreover, FN1 has been described as having a pivotal role in the progression of OvCa cells, 50,51 and is also reported to induce resistance for specific chemotherapeutic agents. 52,53 Although few reports have described a direct association between platinum-resistance and FN1 expression in stromal cells of peritoneal metastasis, signal transduction from FN1 to Akt via integrin and PI3K has been recognized as a critical pathway in cancer progression.…”

Section: Discussionmentioning

confidence: 99%

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

Yoshihara

Kajiyama

Yokoi

et al. 2020

Intl Journal of Cancer

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Peritoneal dissemination of ovarian cancer (OvCa) arises from the surface of the peritoneum, covered by monolayer of mesothelial cells (MCs). Given that both OvCa cells and MCs are present in the same peritoneal metastatic microenvironment, they may establish cell‐to‐cell crosstalk or phenotypic alterations including the acquisition of platinum‐resistance in OvCa cells. Herein, we report how OvCa‐associated mesothelial cells (OCAMs) induce platinum‐resistance in OvCa cells through direct cell‐to‐cell crosstalk. We evaluated mutual associations between OvCa cells and human primary MCs with in vitro coculturing experimental models and in silico omics data analysis. The role of OCAMs was also investigated using clinical samples and in vivo mice models. Results of in vitro experiments show that mesenchymal transition is induced in OCAMs primarily by TGF‐β1 stimulation. Furthermore, OCAMs influence the behavior of OvCa cells as a component of the tumor microenvironment of peritoneal metastasis. Mechanistically, OCAMs can induce decreased platinum‐sensitivity in OvCa cells via induction of the FN1/Akt signaling pathway via cell‐to‐cell interactions. Histological analysis of OvCa peritoneal metastasis also illustrated FN1 expression in stromal cells that are supposed to originate from MCs. Further, we also confirmed the activation of Akt signaling in OvCa cells in contact with TGF‐β1 stimulated peritoneum, using an in vivo mice model. Our results suggest that the tumor microenvironment, enhanced by direct cell‐to‐cell crosstalk between OvCa cells and OCAMs, induces acquisition of platinum‐resistance in OvCa cells, which may serve as a novel therapeutic target for prevention of OvCa peritoneal dissemination.

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Section: Discussionmentioning

confidence: 99%

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

Yoshihara

Kajiyama

Yokoi

et al. 2020

Intl Journal of Cancer

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“…This is a recently emerging subgroup of regulatory proteins which play an important role in many of the classic cancer hallmarks [71]. TGFBI expression was significantly increased in peritoneal tumors compared to primary ovarian tumors [72]. As to OPN , two recent studies have demonstrated that it significantly increased the invasion and proliferation of PDAC cell lines in vitro and their growth in vivo.…”

Section: Discussionmentioning

confidence: 99%

Unique cellular interactions between pancreatic cancer cells and the omentum

Feygenzon¹,

Loewenstein²,

Lubezky³

et al. 2017

PLoS ONE

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Pancreatic cancer is a common cause of cancer-related mortality. Omental spread is frequent and usually represents an ominous event, leading to patient death. Omental metastasis has been studied in ovarian cancer, but data on its role in pancreatic cancer are relatively scarce and the molecular biology of this process has yet to be explored. We prepared tissue explants from human omental fat, and used conditioned medium from the explants for various in vitro and in vivo experiments designed to evaluate pancreatic cancer development, growth, and survival. Mass spectrometry identified the fat secretome, and mRNA array identified specific fat-induced molecular alternations in tumor cells. Omental fat increased pancreatic cancer cellular growth, migration, invasion, and chemoresistance. We identified diverse potential molecules secreted by the omentum, which are associated with various pro-tumorigenic biological processes. Our mRNA array identified specific omental-induced molecular alternations that are associated with cancer progression and metastasis. Omental fat increased the expression of transcription factors, mRNA of extracellular matrix proteins, and adhesion molecules. In support with our in vitro data, in vivo experiments demonstrated an increased pancreatic cancer tumor growth rate of PANC-1 cells co-cultured for 24 hours with human omental fat conditioned medium. Our results provide novel data on the role of omental tissue in omental metastases of pancreatic cancer. They imply that omental fat secreted factors induce cellular reprogramming of pancreatic cancer cells, resulting in increased tumor aggressiveness. Understanding the mechanisms of omental metastases may enable us to discover new potential targets for therapy.

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“…A greater understanding of the mechanisms involved in the progression of ovarian cancer will aid in the discovery of novel molecular prognostic indicators as well as new therapeutic targets. To increase our understanding of the molecular mechanisms involved in ovarian cancer progression and to identify novel therapeutic targets we recently studied the interaction of ovarian cancer and peritoneal cells [3–5]. Keratins K5 and K6c were amongst the proteins that were identified in the ovarian cancer peritoneal cell co-culture secretome by MALDI-TOF/TOF mass spectrometry [5].…”

Section: Introductionmentioning

confidence: 99%

Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance

et al. 2017

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This study investigated the clinical significance of keratin 5 and 6 expression in serous ovarian cancer progression and chemotherapy resistance. KRT5 and KRT6 (KRT6A, KRT6B & KRT6C) gene expression was assessed in publically available serous ovarian cancer data sets, ovarian cancer cell lines and primary serous ovarian cancer cells. Monoclonal antibodies which detect both K5/6 or only K5 were used to assess protein expression in ovarian cancer cell lines and a cohort of high grade serous ovarian carcinomas at surgery (n = 117) and after neoadjuvant chemotherapy (n = 21). Survival analyses showed that high KRT5 mRNA in stage III/IV serous ovarian cancers was significantly associated with reduced progression-free (HR 1.38, P < 0.0001) and overall survival (HR 1.28, P = 0.013) whilst high KRT6 mRNA was only associated with reduced progression-free survival (HR 1.2, P = 0.031). Both high K5/6 (≥ 10%, HR 1.78 95% CI; 1.03−2.65, P = 0.017) and high K5 (≥ 10%, HR 1.90, 95% CI; 1.12−3.19, P = 0.017) were associated with an increased risk of disease recurrence. KRT5 but not KRT6C mRNA expression was increased in chemotherapy resistant primary serous ovarian cancer cells compared to chemotherapy sensitive cells. The proportion of serous ovarian carcinomas with high K5/6 or high K5 immunostaining was significantly increased following neoadjuvant chemotherapy. K5 can be used to predict serous ovarian cancer prognosis and identify cancer cells that are resistant to chemotherapy. Developing strategies to target K5 may therefore improve serous ovarian cancer survival.

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WOMEN IN CANCER THEMATIC REVIEW: Ovarian cancer–peritoneal cell interactions promote extracellular matrix processing

Cited by 23 publications

References 127 publications

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

Ovarian cancer‐associated mesothelial cells induce acquired platinum‐resistance in peritoneal metastasis via the FN1/Akt signaling pathway

Unique cellular interactions between pancreatic cancer cells and the omentum

Keratin 5 overexpression is associated with serous ovarian cancer recurrence and chemotherapy resistance

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