Omental Adipose Tissue–Derived Stromal Cells Promote Vascularization and Growth of Endometrial Tumors

Klopp, Ann H.; Zhang, Yan; Solley, Travis; Amaya-Manzanares, Felipe; Marini, Frank C.; Andreeff, Michael; Debeb, Bisrat G.; Woodward, Wendy A.; Schmandt, Rosemarie; Broaddus, Russell R.; Lu, Karen H.; Kolonin, Mikhail G.

doi:10.1158/1078-0432.ccr-11-1916

Cited by 151 publications

(144 citation statements)

References 49 publications

(64 reference statements)

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“…The omentum contains a population of stromal cells, adipose stromal cells (ASC), which are multipotent mesenchymal stem cells that engraft in tumors and can support cancer progression (4-7). Omentum-derived ASCs (O-ASC) may contribute to the formation of a hospitable environment for the development of ovarian cancer metastasis (8,9). Recently, we showed that O-ASCs promoted proliferation, migration, chemotherapy, and radiation response of ovarian cancer cells (8).…”

Section: Introductionmentioning

confidence: 99%

“…Recently, we showed that O-ASCs promoted proliferation, migration, chemotherapy, and radiation response of ovarian cancer cells (8). Furthermore, O-ASCs recruited to tumors expressed factors that enhanced tumor vascularization, promoted survival, and proliferation of endometrial cancer cells (9). However, the mechanism by which O-ASCs regulate tumor growth and induce chemoresistance is unknown.…”

Section: Introductionmentioning

confidence: 99%

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Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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Omental adipose stromal cells (O-ASC) are a multipotent population of mesenchymal stem cells contained in the omentum tissue that promote endometrial and ovarian tumor proliferation, migration, and drug resistance. The mechanistic underpinnings of O-ASCs' role in tumor progression and growth are unclear. Here, we propose a novel nitric oxide (NO)-mediated metabolic coupling between O-ASCs and gynecologic cancer cells in which O-ASCs support NO homeostasis in malignant cells. NO is synthesized endogenously by the conversion of L-arginine into citrulline through nitric oxide synthase (NOS). Through arginine depletion in the media using L-arginase and NOS inhibition in cancer cells using N G -nitro-L-arginine methyl ester (L-NAME), we demonstrate that patientderived O-ASCs increase NO levels in ovarian and endometrial cancer cells and promote proliferation in these cells. O-ASCs and cancer cell cocultures revealed that cancer cells use O-ASCsecreted arginine and in turn secrete citrulline in the microenvironment. Interestingly, citrulline increased adipogenesis potential of the O-ASCs. Furthermore, we found that O-ASCs increased NO synthesis in cancer cells, leading to decrease in mitochondrial respiration in these cells. Our findings suggest that O-ASCs upregulate glycolysis and reduce oxidative stress in cancer cells by increasing NO levels through paracrine metabolite secretion. Significantly, we found that O-ASCmediated chemoresistance in cancer cells can be deregulated by altering NO homeostasis. A combined approach of targeting secreted arginine through L-arginase, along with targeting microenvironment-secreted factors using L-NAME, may be a viable therapeutic approach for targeting ovarian and endometrial cancers. Cancer Res; 75(2); 456-71. Ó2014 AACR.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

et al. 2015

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“…As one example, the combination of osteogenic potential and targeted delivery of anticancer agents make MSCs a promising option to treat tumor-induced osteolysis (16,17). However, exogenous tissue-derived MSCs, including those from bone marrow, adipose tissues, and umbilical cord, have all shown a tendency to promote rather than inhibit cancers in many circumstances (18)(19)(20)(21)(22)(23). Also, endogenous MSCs are a major source of reactive stromal cells that promote growth and metastasis of cancers (4,24).…”

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confidence: 99%

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Zhao¹,

Gregory²,

Lee³

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Mesenchymal stem or stromal cells (MSCs) have many potential therapeutic applications including therapies for cancers and tissue damages caused by cancers or radical cancer treatments. However, tissue-derived MSCs such as bone marrow MSCs (BM-MSCs) may promote cancer progression and have considerable donor variations and limited expandability. These issues hinder the potential applications of MSCs, especially those in cancer patients. To circumvent these issues, we derived MSCs from transgene-free human induced pluripotent stem cells (iPSCs) efficiently with a modified protocol that eliminated the need of flow cytometric sorting. Our iPSC-derived MSCs were readily expandable, but still underwent senescence after prolonged culture and did not form teratomas. These iPSC-derived MSCs homed to cancers with efficiencies similar to BM-MSCs but were much less prone than BM-MSCs to promote the epithelial-mesenchymal transition, invasion, stemness, and growth of cancer cells. The observations were probably explained by the much lower expression of receptors for interleukin-1 and TGFβ, downstream protumor factors, and hyaluronan and its cofactor TSG6, which all contribute to the protumor effects of BM-MSCs. The data suggest that iPSC-derived MSCs prepared with the modified protocol are a safer and better alternative to BM-MSCs for therapeutic applications in cancer patients. The protocol is scalable and can be used to prepare the large number of cells required for "off-the-shelf" therapies and bioengineering applications.

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“…ASCs with stem cell properties have previously been identified in the bone marrow mesenchyme, skin, hair, dental pulp, kidney, and even peripheral blood (Karaoz et al, 2009). However, adult cells with stem cell properties are safer and have greater practical use, having been employed for over 50 years to replace bone marrow in leukemia and non-hematological diseases without causing malignant transformation (Klopp et al, 2012).During the last few year's isolations of AMSCs from different sources have been reported. It has also been shown promising potential of omental cells for proliferation and differentiation into different cell types (Witowski & Jorres, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…Omentum is considered as a source of ASCs and the non-fatstromal cells in the expanded omental tissue. The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphnodes called milky spots .Omental mesenchymal stem cells (OMSCs), however, are more easily obtainable in large quantities, can be harvested from the patient's own omentum, and able to passage in culture and differentiates into target tissues (Dhanasekaran et al, 213;Klopp et al, 2012). Together, the data suggest that the omentum contains the potent ability of tissue regeneration and may be useful for treatment of various types of diseases involving tissue damages.…”

Section: Introductionmentioning

confidence: 99%

Effect of Placental Extract on Omentum Mesenchymal Stem Cells Differentiation in NMRI Mice

Nezhadfazel¹,

Parivar²,

Roodbari³

et al. 2017

JMBR

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Omentum mesenchymal stem cells (OMSCs) could be induced to differentiate into cell varieties under certain conditions. We studied differentiation of OMSCs induced by using placenta extract in NMRI mice. Mesenchymal stem cells (MSCs) were isolated from omentum and cultured with mice placenta extract. MSCs, were assessed after three passages by flow cytometry for CD90, CD44, CD73, CD105, CD34 markers and were recognized their ability to differentiate into bone and fat cell lines. Placenta extract dose was determined with IC50 test then OMSCs were cultured in DMEM and 20% placenta extract.The cell cycle was checked. OMSCs were assayed on 21 days after culture and differentiated cells were determined by flow cytometry and again processed for flow cytometry. CD90, CD44, CD73, CD105 markers were not expressed, only CD34 was their marker. OMSCs were morphologically observed. Differentiated cells are similar to the endothelial cells. Therefore, to identify differentiated cells, CD31 and FLK1 expression were measured. This was confirmed by its expression. G1 phase of the cell cycle shows that OMSCs compared to the control group, were in the differentiation phase. The reason for the differentiation of MSCs into endothelial cells was the sign of presence of VEGF factor in the medium too high value of as a VEGF secreting source.

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Omental Adipose Tissue–Derived Stromal Cells Promote Vascularization and Growth of Endometrial Tumors

Cited by 151 publications

References 49 publications

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

Nitric Oxide Mediates Metabolic Coupling of Omentum-Derived Adipose Stroma to Ovarian and Endometrial Cancer Cells

MSCs derived from iPSCs with a modified protocol are tumor-tropic but have much less potential to promote tumors than bone marrow MSCs

Effect of Placental Extract on Omentum Mesenchymal Stem Cells Differentiation in NMRI Mice

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