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Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.

ABSTRACT: Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment.Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, preferentially engraft and differentiate into ?-smooth muscle actin-positive myofibroblasts, suggesting their role as "reactive stroma" in ovarian carcinoma development and confirming their potential as a targeted delivery vehicle for the intratumoral production of interferon-? (IFN-?). Mice with ovarian carcinomas then received weekly intraperitoneal injections of IFN-? expressing MSCs.Intraperitoneal injections of IFN-? expressing MSCs resulted in complete eradication of tumors in 70% of treated OVCAR3 mice (P = 0.004) and an increased survival of treated SKOV3 mice compared with controls (P = 0.01). Similar tumor growth control was observed using murine IFN-? delivered by murine MSCs in ID8-R ovarian carcinoma. As a potential mechanism of tumor killing, MSCs produced IFN-?-induced caspase-dependent tumor cell apoptosis.Our results demonstrate that ovarian carcinoma engrafts MSCs to participate in myofibrovascular networks and that IFN-? produced by MSCs intratumorally modulates tumor kinetics, resulting in prolonged survival.

SUBMITTER: Dembinski JL

PROVIDER: S-EPMC3709838 | biostudies-literature | 2013 Jan

REPOSITORIES: biostudies-literature

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Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.

Dembinski Jennifer L JL Wilson Shanna M SM Spaeth Erika L EL Studeny Matus M Zompetta Claudia C Samudio Ismael I Roby Katherine K Andreeff Michael M Marini Frank C FC

Cytotherapy 20130101 1

<h4>Background aims</h4>Many ovarian cancers originate from ovarian surface epithelium, where they develop from cysts intermixed with stroma. The stromal layer is critical to the progression and survival of the neoplasm and consequently is recruited into the tumor microenvironment.<h4>Methods</h4>Using both syngeneic mouse tumors (ID8-R) and human xenograft (OVCAR3, SKOV3) tumor models, we first confirmed that intraperitoneally injected circulating mesenchymal stem cells (MSCs) could target, pre ...[more]

PMID: 23260083

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Project description:Tumor‑stroma interactions serve a crucial role in the development of colorectal cancer (CRC), in which secreted protein acidic and rich in cysteine (SPARC) has been implicated. Due to interactions between cancer and stromal cells [mesenchymal stem cells (MSCs)], SPARC gene expression is markedly upregulated in CRC cells. The present study investigated the role of SPARC in CRC development and its potential as a biomarker. Specifically, the present study examined the association between SPARC expression and clinicopathological characteristics in 42 cases of CRC. SPARC expression in cancer cells was associated with T grade, N grade (TNM classification), stage and poor prognosis. Furthermore, the area of fibroblast‑activating protein‑positive staining around the cancer cells was increased in SPARC‑positive compared with SPARC‑negative cases. Proliferation and wound healing assays in SPARC‑silenced KM12SM cells [short hairpin RNA SPARC (shSPARC)], the reduced SPARC expression of which was demonstrated by reverse transcription‑quantitative PCR, revealed that the proliferative and migratory capacity of shSPARC cells did not differ from that of wild‑type (WT) cells. However, it was markedly reduced when co‑cultured with MSCs. Furthermore, in vivo, immunohistological analysis and RNA sequencing were conducted in an orthotopic implanted mouse model. Tumor growth and lymph node metastasis were markedly suppressed in shSPARC‑transplanted tumors compared with WT‑transplanted tumors, with a more marked suppression observed following shSPARC co‑transplantation with MSCs. Immunohistological examination further revealed that the stromal reaction and epithelial‑mesenchymal transition (EMT) were markedly suppressed in tumors co‑transplanted with shSPARC and MSCs, and these results were consistent with RNA sequencing using RNA extracted from orthotopic tumors. Overall, these results suggested that SPARC expression in CRC cells is dependent on the interaction between cancer cells and stromal cells to induce EMT and promote stromal formation in the tumor microenvironment, suggesting its suitability as a novel target molecule for CRC treatment.

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Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.

Publications

Tumor stroma engraftment of gene-modified mesenchymal stem cells as anti-tumor therapy against ovarian cancer.

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