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Role of mesenchymal cells in the natural history of ovarian cancer: a review.

Touboul C, Vidal F, Pasquier J, Lis R, Rafii A - J Transl Med (2014)

Bottom Line: They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage.The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche.Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hôpital Intercommunal de Créteil, Université Paris Est, UPEC-Paris XII, 12 avenue de Verdun, 94000, Créteil, France. cyril.touboul@gmail.com.

ABSTRACT

Background: Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the tumor microenvironment and its cellular component emerged from studies on the histopathological sequence of changes at the interface between putative tumor cells and the surrounding non-neoplastic tissues during carcinogenesis.

Method: In this review we aimed to describe the pro-tumoral crosstalk between ovarian cancer and mesenchymal stem cells. A PubMed search was performed for articles published pertaining to mesenchymal stem cells and specific to ovarian cancer.

Results: Mesenchymal stem cells participate to an elaborate crosstalk through direct and paracrine interaction with ovarian cancer cells. They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage.

Conclusion: The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche. Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus

Early steps in peritoneal infiltration. Tumor-associated Mesenchymal Cells (TAMCs) constitute a protective niche for ascitic Ovarian Cancer Cells (OCCs) through their inhibition of anti-cancer T cells. They also participate in angiogenesis at metastatic sites by inducing macrophages production of pro-angiogenic cytokines including IL-6, IL-8 and VEGF. Ascitic OCCs may be the primary source of peritoneal metastases. The initiation of peritoneal invasion relies on the ability of OCCs to attach to and to clear the mesothelial cells that constitute the peritoneum. This mesothelial clearance involves integrin- and talin-dependent activation of myosin and allows OCCs to get access to the basement membrane. Bone marrow-derived Mesenchymal Stem Cells (MSCs) are recruited at metastatic sites and favor the infiltration process with the release of secreted factors such as IL-6 and MMP-2. The metalloprotease MMP-2 is also up regulated in OCCs upon binding to mesothelium and leads to improved attachment of tumor cells by modifying the extracellular matrix.
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Fig4: Early steps in peritoneal infiltration. Tumor-associated Mesenchymal Cells (TAMCs) constitute a protective niche for ascitic Ovarian Cancer Cells (OCCs) through their inhibition of anti-cancer T cells. They also participate in angiogenesis at metastatic sites by inducing macrophages production of pro-angiogenic cytokines including IL-6, IL-8 and VEGF. Ascitic OCCs may be the primary source of peritoneal metastases. The initiation of peritoneal invasion relies on the ability of OCCs to attach to and to clear the mesothelial cells that constitute the peritoneum. This mesothelial clearance involves integrin- and talin-dependent activation of myosin and allows OCCs to get access to the basement membrane. Bone marrow-derived Mesenchymal Stem Cells (MSCs) are recruited at metastatic sites and favor the infiltration process with the release of secreted factors such as IL-6 and MMP-2. The metalloprotease MMP-2 is also up regulated in OCCs upon binding to mesothelium and leads to improved attachment of tumor cells by modifying the extracellular matrix.

Mentions: Initial dissemination of OCCs from primary tumor is based on changes in expression of cellular adhesive proteins (Figure 4). Intercellular adhesion in ovarian tumors is mediated by N- and E-cadherin, and cell-matrix adhesion by integrins [127]. Disruption of both cell-cell contact and cell-matrix interactions results in the shedding of single cells or muticellular aggregates into peritoneal cavity. These ascitic OCCs undergo epithelial-to-mesenchymal-transition, resulting in a phenotype with low levels of E-cadherin and higher invasiveness and motility compared to primary tumor cells [128]. They also display CSCs characteristics when clustered in compact spheres, leading to increased chemoresistance and tumorigenesis [99]. They migrate to distant areas following the flow of peritoneal fluid hence the geographical localization of lesions within the abdomen at diagnosis. Ascites fluid comprises more than 200 proteins in its soluble fraction, including LPA, SDF1, cytokines such as RANTES, IL-1, IL-6, IL-8 and IL-10, growth factors (EGF, VEGF, HB-EGF, TGFβ, TNFα and CSF1) and ECM proteins such as collagens I and III [129-136]. It thus constitutes a suitable environment for OCCs survival.Figure 4


Role of mesenchymal cells in the natural history of ovarian cancer: a review.

Touboul C, Vidal F, Pasquier J, Lis R, Rafii A - J Transl Med (2014)

Early steps in peritoneal infiltration. Tumor-associated Mesenchymal Cells (TAMCs) constitute a protective niche for ascitic Ovarian Cancer Cells (OCCs) through their inhibition of anti-cancer T cells. They also participate in angiogenesis at metastatic sites by inducing macrophages production of pro-angiogenic cytokines including IL-6, IL-8 and VEGF. Ascitic OCCs may be the primary source of peritoneal metastases. The initiation of peritoneal invasion relies on the ability of OCCs to attach to and to clear the mesothelial cells that constitute the peritoneum. This mesothelial clearance involves integrin- and talin-dependent activation of myosin and allows OCCs to get access to the basement membrane. Bone marrow-derived Mesenchymal Stem Cells (MSCs) are recruited at metastatic sites and favor the infiltration process with the release of secreted factors such as IL-6 and MMP-2. The metalloprotease MMP-2 is also up regulated in OCCs upon binding to mesothelium and leads to improved attachment of tumor cells by modifying the extracellular matrix.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4197295&req=5

Fig4: Early steps in peritoneal infiltration. Tumor-associated Mesenchymal Cells (TAMCs) constitute a protective niche for ascitic Ovarian Cancer Cells (OCCs) through their inhibition of anti-cancer T cells. They also participate in angiogenesis at metastatic sites by inducing macrophages production of pro-angiogenic cytokines including IL-6, IL-8 and VEGF. Ascitic OCCs may be the primary source of peritoneal metastases. The initiation of peritoneal invasion relies on the ability of OCCs to attach to and to clear the mesothelial cells that constitute the peritoneum. This mesothelial clearance involves integrin- and talin-dependent activation of myosin and allows OCCs to get access to the basement membrane. Bone marrow-derived Mesenchymal Stem Cells (MSCs) are recruited at metastatic sites and favor the infiltration process with the release of secreted factors such as IL-6 and MMP-2. The metalloprotease MMP-2 is also up regulated in OCCs upon binding to mesothelium and leads to improved attachment of tumor cells by modifying the extracellular matrix.
Mentions: Initial dissemination of OCCs from primary tumor is based on changes in expression of cellular adhesive proteins (Figure 4). Intercellular adhesion in ovarian tumors is mediated by N- and E-cadherin, and cell-matrix adhesion by integrins [127]. Disruption of both cell-cell contact and cell-matrix interactions results in the shedding of single cells or muticellular aggregates into peritoneal cavity. These ascitic OCCs undergo epithelial-to-mesenchymal-transition, resulting in a phenotype with low levels of E-cadherin and higher invasiveness and motility compared to primary tumor cells [128]. They also display CSCs characteristics when clustered in compact spheres, leading to increased chemoresistance and tumorigenesis [99]. They migrate to distant areas following the flow of peritoneal fluid hence the geographical localization of lesions within the abdomen at diagnosis. Ascites fluid comprises more than 200 proteins in its soluble fraction, including LPA, SDF1, cytokines such as RANTES, IL-1, IL-6, IL-8 and IL-10, growth factors (EGF, VEGF, HB-EGF, TGFβ, TNFα and CSF1) and ECM proteins such as collagens I and III [129-136]. It thus constitutes a suitable environment for OCCs survival.Figure 4

Bottom Line: They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage.The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche.Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies.

View Article: PubMed Central - PubMed

Affiliation: Department of Obstetrics and Gynecology, Hôpital Intercommunal de Créteil, Université Paris Est, UPEC-Paris XII, 12 avenue de Verdun, 94000, Créteil, France. cyril.touboul@gmail.com.

ABSTRACT

Background: Ovarian cancer is the deadliest gynaecologic malignancy. Despite progresses in chemotherapy and ultra-radical surgeries, this locally metastatic disease presents a high rate of local recurrence advocating for the role of a peritoneal niche. For several years, it was believed that tumor initiation, progression and metastasis were merely due to the changes in the neoplastic cell population and the adjacent non-neoplastic tissues were regarded as bystanders. The importance of the tumor microenvironment and its cellular component emerged from studies on the histopathological sequence of changes at the interface between putative tumor cells and the surrounding non-neoplastic tissues during carcinogenesis.

Method: In this review we aimed to describe the pro-tumoral crosstalk between ovarian cancer and mesenchymal stem cells. A PubMed search was performed for articles published pertaining to mesenchymal stem cells and specific to ovarian cancer.

Results: Mesenchymal stem cells participate to an elaborate crosstalk through direct and paracrine interaction with ovarian cancer cells. They play a role at different stages of the disease: survival and peritoneal infiltration at early stage, proliferation in distant sites, chemoresistance and recurrence at later stage.

Conclusion: The dialogue between ovarian and mesenchymal stem cells induces the constitution of a pro-tumoral mesencrine niche. Understanding the dynamics of such interaction in a clinical setting might propose new therapeutic strategies.

No MeSH data available.


Related in: MedlinePlus