Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance<i>via</i>a BMP4/HH signaling loop

Coffman, Lan; Choi, Yun Jung; McLean, Karen; Allen, Benjamin L.; Magliano, Marina Pasca di; Buckanovich, Ronald J.

doi:10.18632/oncotarget.6870

Cited by 114 publications

(111 citation statements)

References 54 publications

(78 reference statements)

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“…The distinct expression profile of CA‐MSCs corresponds with unique protumorigenic functions: (a) CA‐MSCs increase the CSC pool as marked by increased levels of ALDH and enhanced tumor sphere formation , and CA‐MSCs enhance (b) tumor growth and (c) chemotherapy resistance . Therefore, we determined if cancer stimulated OM MSCs classified as CA‐MSCs also developed CA‐MSC‐associated protumorigenic functions.…”

Section: Resultsmentioning

confidence: 99%

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma

et al. 2018

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Carcinoma‐associated mesenchymal stem cells (CA‐MSCs) are critical stromal progenitor cells within the tumor microenvironment (TME). We previously demonstrated that CA‐MSCs differentially express bone morphogenetic protein family members, promote tumor cell growth, increase cancer “stemness,” and chemotherapy resistance. Here, we use RNA sequencing of normal omental MSCs and ovarian CA‐MSCs to demonstrate global changes in CA‐MSC gene expression. Using these expression profiles, we create a unique predictive algorithm to classify CA‐MSCs. Our classifier accurately distinguishes normal omental, ovary, and bone marrow MSCs from ovarian cancer CA‐MSCs. Suggesting broad applicability, the model correctly classifies pancreatic and endometrial cancer CA‐MSCs and distinguishes cancer associated fibroblasts from CA‐MSCs. Using this classifier, we definitively demonstrate ovarian CA‐MSCs arise from tumor mediated reprograming of local tissue MSCs. Although cancer cells alone cannot induce a CA‐MSC phenotype, the in vivo ovarian TME can reprogram omental or ovary MSCs to protumorigenic CA‐MSCs (classifier score of >0.96). In vitro studies suggest that both tumor secreted factors and hypoxia are critical to induce the CA‐MSC phenotype. Interestingly, although the breast cancer TME can reprogram bone marrow MSCs into CA‐MSCs, the ovarian TME cannot, demonstrating for the first time that tumor mediated CA‐MSC conversion is tissue and cancer type dependent. Together these findings (a) provide a critical tool to define CA‐MSCs and (b) highlight cancer cell influence on distinct normal tissues providing powerful insights into the mechanisms underlying cancer specific metastatic niche formation. S tem C ells 2019;37:257–269

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Section: Resultsmentioning

confidence: 99%

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma

et al. 2018

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“…Our previous work demonstrates that axillary xenografts with ovarian cancer cell lines SKOV3 and CAOV3 do not form metastatic disease (13, 28). We next utilized primary patient derived ovarian tumor cells in an axillary xenograft model.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that co-injection of cancer cells with carcinoma associated mesenchymal stem cells (CA-MSC) can promote cancer growth via the formation of multiple components of the human tumor microenvironment though these xenografts do not spontaneously develop metastasis (13, 28). We sought to determine if a human microenvironment can increase ovarian cancer metastasis.…”

Section: Resultsmentioning

confidence: 99%

New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination

Coffman

Burgos-Ojeda

et al. 2016

Translational Research

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Emerging evidence suggest that many high grade serous ‘ovarian’ cancers (HGSOC) start in the fallopian tube. Cancer cells are then recruited to the ovary and then spread diffusely through the abdomen. The mechanism of ovarian cancer spread was thought to be largely due to direct shedding of tumor cells into the peritoneal cavity with vascular spread being of limited importance. Recent work challenges this dogma, suggesting hematogenous spread of ovarian cancer may play a larger role in ovarian cancer cell metastasis than previously thought. One reason the role of vascular spread of ovarian cancer has not been fully elucidated is the lack of easily accessible models of vascular ovarian cancer metastasis. Here we present three metastatic models of ovarian cancer which confirm the ability of ovarian cancer to hematogenously spread. Strikingly, we observe a high rate of metastasis to the ovary with the development of ascites in these models. Interestingly, oophorectomy resulted in a complete loss of peritoneal metastases and ascites. Taken together our data indicates that hematogenously disseminated HGSOC cells have a unique tropism for the ovary and that hematogenous spread in ovarian cancer may be more common than appreciated. Furthermore our studies support a critical role for the ovary in promoting HGSOC cell metastasis to the abdomen. The models developed here represent important new tools to evaluate both the mechanism of cancer cell recruitment to the ovary and to understand and target key steps in ovarian cancer metastasis.

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“…The microenvironment of cancer is complicated and can maintain stable survival advantages of PaC cells despite various perturbations [20, 21]. When the environment is not optimal, PaC cells can mediate adaptive changes such as stimulation of tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Periostin promotes tumor angiogenesis in pancreatic cancer via Erk/VEGF signaling

Liu

Gao

et al. 2016

Oncotarget

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Pancreatic cancer (PaC) consists of a bulk of stroma cells which contribute to tumor progression by releasing angiogenic factors. Recent studies have found that periostin (POSTN) is closely associate with the metastatic potential and prognosis of PaC. The purpose of this study is to determine the role of POSTN in tumor angiogenesis and explore the precise mechanisms. In this study, we used lentiviral shRNA and human recombinant POSTN protein (rPOSTN) to negatively and positively regulate POSTN expression in vitro. We found that increased POSTN expression promoted the tubule formation dependent on human umbilical vein endothelial cells (HUVECs). Moreover, knockdown of POSTN in PaC cells reduced tumor growth and VEGF expression in vivo. In accordance with these observations, we found that Erk phosphorylation and its downstream VEGF expression were upregulated achieved in rPOSTN-treated groups, opposing results were obversed in POSTN-slienced group. Meanwhile, Erk inhibitor SCH772984 significantly decreased VEGF expression as well as tubule formation of HUVECs in rPOSTN-treated PaC cells. Taken together, these findings suggest that POSTN promotes tumor angiogenesis via Erk/VEGF signaling in PaC and POSTN may be a new target for cancer anti-vascular treatment.

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Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistanceviaa BMP4/HH signaling loop

Cited by 114 publications

References 54 publications

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma

Ovarian Carcinoma-Associated Mesenchymal Stem Cells Arise from Tissue-Specific Normal Stroma

New models of hematogenous ovarian cancer metastasis demonstrate preferential spread to the ovary and a requirement for the ovary for abdominal dissemination

Periostin promotes tumor angiogenesis in pancreatic cancer via Erk/VEGF signaling

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