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ORIGINAL ARTICLE
Year : 2014  |  Volume : 10  |  Issue : 1  |  Page : 159-164

Adipose derived stem cells isolated from omentum: A novel source of chemokines for ovarian cancer growth


1 Shiraz Institute for Cancer Research, Departments of Immunology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
2 Shiraz Institute for Cancer Research, School of Medicine, Shiraz University of Medical Sciences, Iran
3 Department of Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran

Date of Web Publication23-Apr-2014

Correspondence Address:
Abbas Ghaderi
Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences, School of Medicine, Shiraz
Iran
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.131451

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 > Abstract 

Background: The main site of ovarian cancer metastasis is the omentum. Omental adipose tissue is known for contribution to the tumor growth and metastasis through different mechanisms.
Aims: In the present study, adipose derived stem cells (ASCs) were isolated from the omentum of patients with ovarian cancer and those with ovarian cysts and the expression of chemokines, chemokine receptors and cytokines were analyzed.
Materials and Methods: ASCs were isolated from omental adipose tissues obtained of 10 ovarian cancer and 25 ovarian benign cyst patients. Our investigations were done by quantitative real time-polymerase chain reaction, flowcytometry, western blot and also enzyme-linked immunosorbent assay.
Result: Expression of CXCL-10 and CCR5 showed statistically significant difference between omentum derived ASCs of ovarian cancer patients compared with those with benign cysts (P < 0.05). Expression of interleukin-10 also detected in the supernatant of cultured malignant ASCs.
Conclusion: Omental adipose tissue may play crucial roles for tumor promotion through the expression of tumor promoting chemokines. Accordingly, tumor surrounding adipose tissue may be a novel target for immunotherapy of cancer.

 > Abstract in Chinese 

网膜分离的脂肪干细胞:卵巢癌生长趋化因子的新来源
背景:卵巢癌转移的主要部位是网膜。大网膜脂肪组织在肿瘤的生长和转移上贡献巨大,通过不同的机制。
目的:在本研究中,脂肪干细胞(ASCs)在卵巢癌与卵巢囊肿患者的网膜中分离出来,并对其趋化因子表达,趋化因子受体和细胞因子进行了分析。
材料和方法:从10例卵巢癌和25例卵巢良性囊肿患者的大网膜脂肪组织中分离出脂肪干细胞ASCs。我们的研究,通过实时定量聚合酶链反应,流式细胞仪,蛋白免疫印迹法和酶联免疫吸附测定法。
结果:卵巢癌与良性囊肿患者之间网膜脂肪干细胞CXCL10和CCR5的表达差异有统计学意义(P<0.05)。在培养的恶性脂肪干细胞上清液中也检测到了白细胞介素10的表达。
结论:大网膜脂肪组织可以通过肿瘤促进趋化因子的表达在肿瘤促进上发挥重要的作用。因此,肿瘤周围的脂肪组织可能是肿瘤免疫治疗的新靶点。
关键词:脂肪干细胞,卵巢癌,卵巢囊肿,网膜


Keywords: Adipose derive stem cells, ovarian cancer, ovarian cyst, omentum


How to cite this article:
Rezaeifard S, Razmkhah M, Robati M, Momtahan M, Ghaderi A. Adipose derived stem cells isolated from omentum: A novel source of chemokines for ovarian cancer growth. J Can Res Ther 2014;10:159-64

How to cite this URL:
Rezaeifard S, Razmkhah M, Robati M, Momtahan M, Ghaderi A. Adipose derived stem cells isolated from omentum: A novel source of chemokines for ovarian cancer growth. J Can Res Ther [serial online] 2014 [cited 2019 Sep 20];10:159-64. Available from: http://www.cancerjournal.net/text.asp?2014/10/1/159/131451


 > Introduction Top


Numerous studies have focused on the role of mesenchymal stem cells (MSCs) in solid tumors. The directed tropism of MSCs for tumor microenvironment was the main reason for the studies investigating the importance of MSCs on tumor growth. [1] In addition, the immunomodulatory effects of MSCs on down-regulation anti-tumor immune responses underlines more evidences for the crucial role of MSCs in tumor promotion. [2] MSCs derived soluble factors such as indolamine 2,3-dioxygenase, [3] prostaglandin E2 and transforming growth factor-β1 (TGFβ1), [4] along with direct cell to cell contact [5] are main mechanisms of immune-modulatory functions of MSCs. Moreover, MSCs mediate their tumor promoting effects through producing a variety of cytokines and growth factors [6] such as interleukin-6 (IL-6), [7] CCL5 (RANTES) [8] and CXCL-12 (stromal cell-derived factor-1 [SDF-1]). [9] High expression of CXCR4 was shown in poorly differentiated region of papillary thyroid carcinoma. [10] Furthermore, this chemokine receptor is pivotal for angiogenesis and therapeutic resistance of glioblastoma stem-like cells of rat RG2 glioblastoma. [11] Chemokine/chemokine receptor intractions such as CXCL-12/CXCR4 [12] and CCL5/CCR5 promote tumor growth and metastasis. [13] Secretion by adipose derived stem cells (ASCs) including the angiogenic factors have previously been reported. [14] ASCs can penetrate into tumor vessels and contribute to the promotion of tumor growth. It has been reported that tissue resident ASCs are important sources for the production of CXCL-12 in tumor site, which facilitate the tumor growth, invasion and metastasis. [9] CCL-2 or monocyte chemoattractant protein-1 (MCP-1) is also expressed by cells presented in tumor site such as MSCs other than tumor cells in breast carcinoma. [15] Bone marrow derived MSCs recruited to the tumor sites are distinct in their expression profile from their normal counterparts in ovarian cancer patients compared to the healthy individuals. These cells seem to promote tumor growth more effectively than normal MSCs, which are mediated through increasing the number of cancer stem cells. [1] Subcutaneous ASCs are also different in their tumor promoting effects compared to their counterparts derived from visceral adipose tissue. It has been proposed that omenmtal ASCs contribute to the tumor vascularization, promotion and metastasis of endometrial tumors. [16] Herein, the chemokines and chemokines receptors profile (CXCL-12, CXCR4, CXCL-10, CXCR3, CCL-5, CCR5, CCL-2, IL-4 and IL-10) of ASCs, which isolated from the omental adipose tissue of patients with ovarian cancer and ovarian cysts, are characterized.


 > Materials and Methods Top


ASCs were isolated from the omentum of 10 Southern Iranian patients with ovarian cancer. Patients were not undergoing any clinical intervention such as chemotherapy before obtaining adipose tissues of omentum. The mean and median ages of patients were 39.8 ± 19.6 and 42.5, respectively. 20% of patients were diagnosed with pathological Stage I, 70% with pathological Stage III and 1% with pathological Stage IV. The data of ovarian cancer ASCs were compared with ASCs isolated from omentum derived adipose tissue of 25 patients with benign cysts. The mean and median ages of individuals with benign cysts were 43.5 ± 19.9 and 43, respectively. All samples were used after giving consent and current study has been approved by Ethical Committee of Shiraz University of Medical Sciences.

Fragments of adipose tissue were washed with phosphate buffered saline, minced in small pieces and digested with collagenase Type I (GIBCO, USA) at 37°C. The digested material was centrifuged and the pellet including the adherent stromal cells was resuspended in DMEM culture medium (GIBCO, USA) containing 10% fetal bovine serum (GIBCO, USA) and 1% penicillin/streptomycin (Biosera, UK). Non-adherent cells were discarded after being allowed to culture for 24 h. The adherent cells were cultured by changing medium every 4 days and harvested in passage 3-5 in order to have a homogenic population.

In differentiation assay, ASCs has been differentiated to osteocytes, 1 × 10 5 passage 3 ASCs were cultured in 4-well tissue culture plates. When cultures were 60-80% confluent, ASCs were tested for osteogenic differentiation using osteogenesis differentiation kit (STEMPRO Osteogenesis Differentiation Kit, GIBCO, USA). Osteogenic differentiation was assessed on days 7, 14 and 21 by quantitative real time-polymerase chain reaction (qRT-PCR) method for the expression of an osteogenic specific gene, bone morphogenetic protein 2 (BMP-2) and calcium deposition in the differentiated cells.

Total ribonucleic acid (RNA) was extracted from ASCs using TRizol (Invitrogen, Germany) and chloroform (Merck, Germany). Complementary deoxyribonucleic acid (cDNA) was synthesized from the extracted RNAs using the cDNA synthesis kit based on the manufacturer's instructions (Fermentas, Lithuania). The quantities of IL-4, IL-10, CXCL-10, CXCR3, CXCL-12 and CXCR4 gene transcripts were determined using a Bio-Rad thermal cycler (Chromo 4 RT PCR Detector, Bio-Rad, USA) for qRT-PCR. Each PCR reaction was carried out in a final volume of 20 μl that contained 2 μl cDNA, 10 μl of 2X SYBR Green Master Mix (Fermentas, Lithuania), 0.3 μl of each 10 pmol forward and reverse primers and 7.4 μl diethylpyrocarbonate treated water. PCR amplification was done in 50 cycles using the following program: 95°C for 10 min, 95°C for 15 s, 56°C for 20 s and 60°C for 1 min. All data were compared with those from beta actin housekeeping gene.

For flow cytometry analysis, ASCs were harvested using dissociation solution (Sigma, USA). For ASCs immunophenotyping, harvested cells (5 × 10 6 ) were washed twice with PBS and stained with phycoerythrin (PE)-conjugated mouse anti-human CD44, CD105 and CD166 (BD Biosciences, USA) and fluorescein isothiocyanate (FITC)-conjugated mouse anti-human CD14, CD34 and CD45 (BD Biosciences, USA). For intracellular staining, harvested ASCs were incubated with Brefeldin (BD Biosciences, USA) for 5 h. Cells were centrifuged and the resulted cell pellet was incubated with 1% cell fix and then 0.2% saponin. Afterward, cells were stained with 5 μl PE-conjugated mouse anti-human CCL-5, CXCL-10, CCL-2, CXCR4 and FITC-conjugated mouse anti-human CCR5 antibodies (BD Biosciences, USA). Cells were stained with FITC- or PE-labeled mouse immunoglobulin G (BD Biosciences, USA) as negative controls. After 30 min incubation at room temperature, cells were washed twice with PBS. Approximately, 10,000 events were collected on a four colors Becton Dickinson FACS Vantage instrument and further analyzed using WINMDI software version 2.8 (Scripps Research Institute, La Jolla, CA, USA).

For western blot, proteins were extracted from ASCs using 1 ml radio immunoprecipitation assay buffer, 10 μl PMSF (Fluka, USA) and 1 μl protease inhibitor Cocktail (Sigma, USA). Proteins were separated by SDS-PAGE gel and blotted on PVDF membrane (Biorad, USA), which was then blocked in 5% non-fat skim milk in PBS with 0.1% Tween 80. Blots were incubated with rabbit anti-SDF-1 (Abcam, Cambridge, MA) or mouse anti-β-actin antibodies (Abcam, Cambridge, USA) and then further incubated with horseradish peroxidase-conjugated anti-rabbit or anti-mouse secondary antibodies (Abcam, Cambridge, USA). Finally, blots were observed through enzyme-linked chemiluminescence using the SuperSignal West Pico chemiluminescence kit (Pierce).

The presence of IL-10 was measured by the enzyme-linked immunosorbent assay kit (BenderMed Systems, Austria) in the culture supernatants (SNs) of ASCs harvested at day 7 post culture and in the isolated sera from patients diagnosed with ovarian cancer and ovarian cysts as described by manufacturer procedure.

Expressions of IL-4, IL-10, CXCR3, CXCR4, CXCL-10, CXCL-12 messenger RNAs (mRNAs) in ASCs isolated from patients were determined using 2 -∆CT method. Analysis of gene expression between malignant and benign patients with the pathological information of the patients was regarded significant if P < 0.05 using the Mann-Whitney non-parametric test. Graphs were presented using GraphPad Prism 5 (GraphPad Software, San Diego, CA,USA).


 > Results Top


ASCs were appeared with spindle-shaped morphology in the culture as shown in [Figure 1]a. They were characterized as MSCs through differentiation into osteocytes and using flow cytometry analysis. Results of osteocyte differentiation demonstrated the accumulation of calcium in the culture [Figure 1]b. Total RNA was extracted from ASCs at different days of differentiation and the mRNA expression of BMP-2 was tested on days 7, 14 and 21 by qRT-PCR and shown the osteogenic differentiation of ASCs [Figure 2].
Figure 1: (a) Adipose derived stem cells in culture at passage 3. (b) Accumulation of calcium in culture after osteogenic differentiation

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Figure 2: Expression of morphogenetic protein-2 in adipose derived stem cells at various days of osteocyte differentiation. Data were shown as the mean of 2-ÄÄCT

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The flow cytometry analysis for stem cell differentiation markers showed that ASCs were highly positive for CD44 (95.88%), CD105 (70%) and CD166 (84.46%). They were negative (100% of all ASCs) for the expressions of CD14, CD34 and CD45 [Figure 3].
Figure 3: The flow cytometric characteristics of adipose derived stem cells for the expression of CD44, CD166, CD105, CD14, CD34 and CD45

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mRNA expression of IL-4, IL-10, CXCL-12 (SDF-1), CXCR4, CXCL-10 (IP-10) and CXCR3 in ASCs isolated from adipose tissue of omentum are shown in [Figure 4]. As a result, IL-4, CXCR3 and CXCL-12 had lower mRNA expression whereas CXCL-10, IL-10 and CXCR4 had more mRNA expression in ovarian cancer patients compared with those with benign ovarian cysts. CXCL-10 showed 4-fold higher mRNA expression in ovarian cancer patients. These differences were not statistically significant (P > 0.05).
Figure 4: Expression of chemokine and chemokine receptors in adipose derived stem cells of patients. Data were shown as the median of 2-ΔCT × 103 (P>0.05 for all)

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The flow cytometry analysis for the expression of CCL-5 (RANTES), CCL-2 (MCP-1), CXCL-10 (IP-10), CCR5 and CXCR4 is presented in [Figure 5]. No significant different was found in the expressions of CCL-5, CCL-2 and CXCR4. CCR5 and CXCL-10 had statistically significant higher expression in malignant samples versus benign ASCs (P = 0.01 and 0.0008, respectively). Accordingly, CCR5 showed 82.5-fold and CXCL-10 had 4.8-fold higher expression in ovarian cancer ASCs and the mean ± standard error of the mean (SEM) for CCR5 was 8.25 ± 3.95 for malignant samples and 0.1 ± 0.07 for ASCs isolated from benign cysts. Mean ± SEM for IP-10 was 33.26 ± 7.2 in malignant samples and 7.07 ± 3.72 in benign ASCs.

As depicted in [Figure 6], no detectable level of CXCL-12 (SDF-1) protein was observed in omentum derived ASCs of ovarian cancer and benign cyst patients as compared to protein extracted from SKOV3 (Sloan-Kettering HER2 3 + Ovarian Cancer) cell line.
Figure 5: The schematic representation from flow cytometry analysis of the expression of chemokines and chemokine receptors (intracellular staining) in adipose derived stem cells of (a) one patient with ovarian cancer (b) one patient with ovarian benign cyst

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Figure 6: Result of western blot analysis for beta actin and CXCL-12 (stromal cell-derived factor-1) in protein extracts from adipose derived stem cells that isolated from patients with ovarian cancer, benign cyst and one ovarian cancer cell line, SKOV3

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IL-10 concentration in culture SN of ASCs isolated from omental adipose tissue of ovarian cancer patients was higher than patients with benign cyst. Mean ± SEM for IL-10 was 0.07 ± 0.008 in culture SN of ASCs from ovarian cancer patients and 0.06 ± 0.003 in culture SN of benign ASCs. However, this difference was not statistically significant (P >0.05).


 > Discussion Top


Omentum is a large fat pad, which covers the bowel and acts as an endocrine organ and energetic lipid source. It is the main site of ovarian cancer metastasis and most of women with serous ovarian cancer have omental metastases. Thus, omental adipocytes may produce factors responsible for the metastasis of ovarian cancer cells to the omentum. Performing a cytokine array for omental adipocytes has showed that IL-8, IL-6, CCL-2, tissue inhibitor of metalloproteinases-1 and adiponectin are produced in large quantities by omental adipocytes. They proposed that omental adipocytes provide fatty acids and thus energy for cancer cells and their growth. It seems that the role of omental adipocytes is not limited to ovarian cancer and may happen in other malignancies with adipocyte - rich environment and abdominal metastases such as breast cancer. [17] Ovarian cancer cells stimulate human ASCs and induce the production of TGFβ1, which result in TGFβ1 receptor activation and CXCL-12 production by ASCs in an autocrine manner this cytokine increases carcinoma cell growth and angiogenesis. [18] Furthermore, subcutaneous derived ASCs can produce CXCL-12 which induces the expression of CXCR4 on gastric cancer cells and cause the growth, migration and invasion of cancer cells. [19] ASCs derived from breast adipose tissue also seem to have crucial roles in breast carcinoma growth and metastasis. [9] ASCs from breast cancer patients have the ability to facilitate tumor angiogenesis and metastasis. These cells can produce high amount of growth factors, IL-8, CXCL-12 and have high proliferative capacity compared to their healthy counterparts. [9],[20] Existence of ASCs in tumor stroma of the breast may induce tumor infiltrating T lymphocytes toward the regulatory T cells and suppress the anti-tumor immune responses by production of anti-inflammatory cytokines such as IL-10, TGF-β and IL-4. [21] Thus, in tumor microenvironment ASCs may appear as great supporters for tumor cell growth by restraining anti-tumor immune responses.

In this study which, to the best of our knowledge, is the first to characterize ASCs from omentum of patients with ovarian cancer as well as benign cysts, expression of some important chemokines, chemokine receptors and cytokines were investigated. Evaluation of omentum derived ASCs showed the expression of CXCL-10, CXCR3, CCL-5, CCR5, CCL-2, CXCR4 and the mRNA of CXCL-12 in ASCs of patients with ovarian cancer and ovarian benign cysts. Interestingly, these differences were statistically significant for expression of CCR5 and CXCL-10. It appears that CXCL-10 has significant role for pathogenesis of ovarian carcinoma especially when we recently detected higher expression of CXCL-10 in peripheral blood of patients with ovarian cancer (unpublished data). Expression of CXCL-10 is reported in other type of tumors including colorectal and breast cancers. [22],[23] In nasal NK/T-cell lymphoma, CXCL-10 leads to cell invasion through its receptor CXCR3. [24] Other investigation have illustrated the expression of both CXCR3 and CXCL-10 in breast cancer cell lines. [25] Furthermore, there is a report that showed CXCR3 binding to CXCL-10 led to colon cancer migration, calcium mobilization, Protein Kinase B (PKB) activation and ultimately induction of matrix metalloproteinase-2 (MMP-2) and MMP-9 production. [26] Thus, CXCL-10 secretion by ASCs in ovarian cancer patients may cause ovarian cancer cell migration by induction of MMP-2 and MMP-9 production.

CXCL-10 is reverse-correlated with the expression of vascular endothelial growth factor and is linked to the angiostatic activity. [27] Besides, it has been reported that this chemokine can regulate the recruitment of CXCR3 + T cells in tumor stroma [22] or the anatomic site of graft-versus-host disease. [28] Increasing number of Foxp3 + IL-17 + T cells, which highly express TGF-β, CXCR3 and CCR6 were found in colorectal cancer tissue. [29] Furthermore, CD8 + CXCR3 + cells were known with immunomodulatory effects through producing IL-10. [30] Regarding these reports and the data of our study, we hypothesized that CXCL-10 in ASCs of omentum may cause the recruitment of CXCR3 + regulatory T cells. In addition, omentum derived ASCs, through the expression of immunomodulatory cytokines such as IL-10, can even induce the infiltrated CXCR3 + T cells toward the T regulatory cells in tumor site. Furthermore, IL-10 is a potent inhibitor of antigen presentation and major histocompatibility complex (MHC) class II expression as well as it inhibits the up regulation of co-stimulatory molecules CD80 and CD86 [31] and hence it may down regulate anti-ovarian tumor response.

There are many studies on the expression of MCP-1 (CCL2) and RANTES (CCL5) in breast tumor samples. [15] CCL5/CCR5 axis promotes cell migration and invasion in breast cancer, oral cancer cells. [32],[33] This ligand and receptor interaction increased the migration and expression of MMP-3 in human chondrosarcomal cells. [34] Therefore, it is assumed that CCR5 production by ASCs may increase the migration of ovarian cancer cells through the expression of MMP-3.


 > Conclusion Top


Results of the present study and our previous investigations indicate adipose tissue as a source for several important chemokines and anti-inflammatory cytokines and consequently an energy supply for tumor growth, migration and metastasis. Tumor cells, stromal cells and immune cells may construct a vicious cycle in tumor stroma, which ultimately leads to the tumor promotion. Thus, anti-tumor therapeutic strategies will be more successful when target all these three aspects.


 > Acknowledgments Top


The authors like to thank all ovary cancer and benign cyst patients who participated in the present study. This work was financially supported by Shiraz University of Medical Sciences {Grant No. 89-5300} and Shiraz Institute for Cancer Research {ICR-100-504}.

 
 > References Top

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34.Tang CH, Yamamoto A, Lin YT, Fong YC, Tan TW. Involvement of matrix metalloproteinase-3 in CCL5/CCR5 pathway of chondrosarcomas metastasis. Biochem Pharmacol 2010;79:209-17.  Back to cited text no. 34
    


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