Altered features and increased chemosensitivity of human breast cancer cells mediated by adipose tissue-derived mesenchymal stromal cells

BMC Cancer

Lucia Kucerova¹  Svetlana Skolekova¹  Miroslava Matuskova¹  Martin Bohac²  Zuzana Kozovska¹ 

[1] Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava, Slovakia

[2] Institute of Histology and Embryology, Faculty of Medicine, Comenius University, Bratislava, Slovakia

关键词: Cytokine profile;    Epithelial-to-mesenchymal transition;    Proliferation;    Chemoresistance;    Human breast cancer;    Adipose tissue-derived mesenchymal stromal cells;   

Others  :  1079458
DOI  :  10.1186/1471-2407-13-535

 received in 2013-06-27, accepted in 2013-11-03,  发布年份 2013

【 摘 要 】

Background

Mesenchymal stromal cells (MSCs) represent heterogeneous cell population suitable for cell therapies in regenerative medicine. MSCs can also substantially affect tumor biology due to their ability to be recruited to the tumor stroma and interact with malignant cells via direct contacts and paracrine signaling. The aim of our study was to characterize molecular changes dictated by adipose tissue-derived mesenchymal stromal cells (AT-MSCs) and the effects on drug responses in human breast cancer cells SKBR3.

Methods

The tumor cells were either directly cocultured with AT-MSCs or exposed to MSCs-conditioned medium (MSC-CM). Changes in cell biology were evaluated by kinetic live cell imaging, fluorescent microscopy, scratch wound assay, expression analysis, cytokine secretion profiling, ATP-based viability and apoptosis assays. The efficiency of cytotoxic treatment in the presence of AT-MSCs or MSCs-CM was analyzed.

Results

The AT-MSCs altered tumor cell morphology, induced epithelial-to-mesenchymal transition, increased mammosphere formation, cell confluence and migration of SKBR3. These features were attributed to molecular changes induced by MSCs-secreted cytokines and chemokines in breast cancer cells. AT-MSCs significantly inhibited the proliferation of SKBR3 cells in direct cocultures which was shown to be dependent on the SDF-1α/CXCR4 signaling axis. MSC-CM-exposed SKBR3 or SKBR3 in direct coculture with AT-MSCs exhibited increased chemosensitivity and induction of apoptosis in response to doxorubicin and 5-fluorouracil.

Conclusions

Our work further highlights the multi-level nature of tumor-stromal cell interplay and demonstrates the capability of AT-MSCs and MSC-secreted factors to alter the anti-tumor drug responses.

【 授权许可】

   
2013 Kucerova et al.; licensee BioMed Central Ltd.

【 图 表 】

Figure 1.

Figure 2.

Figure 3.

Figure 4.

Figure 5.

【 参考文献 】

• [1]Nelson HD, Zakher B, Cantor A, Fu R, Griffin J, O'Meara ES, Buist DS, Kerlikowske K, van Ravesteyn NT, Trentham-Dietz A, et al.: Risk factors for breast cancer for women aged 40 to 49 years: a systematic review and meta-analysis. Ann Intern Med 2012, 156:635-648.
• [2]Egeblad M, Nakasone ES, Werb Z: Tumors as organs: complex tissues that interface with the entire organism. Dev Cell 2010, 18:884-901.
• [3]Hanahan D, Coussens LM: Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 2012, 21:309-322.
• [4]Zhao M, Dumur CI, Holt SE, Beckman MJ, Elmore LW: Multipotent adipose stromal cells and breast cancer development: Think globally, act locally. Mol Carcinog 2010, 49:923-927.
• [5]Donnenberg VS, Zimmerlin L, Rubin JP, Donnenberg AD: Regenerative therapy after cancer: what are the risks? Tissue Eng Part B Rev 2010, 16:567-575.
• [6]Zimmerlin L, Donnenberg AD, Rubin JP, Basse P, Landreneau RJ, Donnenberg VS: Regenerative therapy and cancer: in vitro and in vivo studies of the interaction between adipose-derived stem cells and breast cancer cells from clinical isolates. Tissue Eng Part A 2011, 17:93-106.
• [7]Schaffler A, Buchler C: Concise review: adipose tissue-derived stromal cells–basic and clinical implications for novel cell-based therapies. Stem Cells 2007, 25:818-827.
• [8]Ciavarella S, Dominici M, Dammacco F, Silvestris F: Mesenchymal stem cells: a new promise in anticancer therapy. Stem Cells Dev 2011, 20:1-10.
• [9]Strioga M, Viswanathan S, Darinskas A, Slaby O, Michalek J: Same or not the same? Comparison of adipose tissue-derived versus bone marrow-derived mesenchymal stem and stromal cells. Stem Cells Dev 2012, 21:2724-2752.
• [10]Kidd S, Spaeth E, Watson K, Burks J, Lu H, Klopp A, Andreeff M, Marini FC: Origins of the tumor microenvironment: quantitative assessment of adipose-derived and bone marrow-derived stroma. PLoS One 2012, 7:e30563.
• [11]El-Haibi CP, Karnoub AE: Mesenchymal stem cells in the pathogenesis and therapy of breast cancer. J Mammary Gland Biol Neoplasia 2010, 15:399-409.
• [12]Kucerova L, Skolekova S: Tumor microenvironment and the role of mesenchymal stromal cells. Neoplasma 2013, 60:1-10.
• [13]Mishra PJ, Humeniuk R, Medina DJ, Alexe G, Mesirov JP, Ganesan S, Glod JW, Banerjee D: Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res 2008, 68:4331-4339.
• [14]Hall B, Dembinski J, Sasser AK, Studeny M, Andreeff M, Marini F: Mesenchymal stem cells in cancer: tumor-associated fibroblasts and cell-based delivery vehicles. Int J Hematol 2007, 86:8-16.
• [15]Spaeth EL, Dembinski JL, Sasser AK, Watson K, Klopp A, Hall B, Andreeff M, Marini F: Mesenchymal stem cell transition to tumor-associated fibroblasts contributes to fibrovascular network expansion and tumor progression. PLoS One 2009, 4:e4992.
• [16]Li HJ, Reinhardt F, Herschman HR, Weinberg RA: Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2012, 2:840-855.
• [17]Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R, Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 2007, 449:557-563.
• [18]Martin FT, Dwyer RM, Kelly J, Khan S, Murphy JM, Curran C, Miller N, Hennessy E, Dockery P, Barry FP, et al.: Potential role of mesenchymal stem cells (MSCs) in the breast tumour microenvironment: stimulation of epithelial to mesenchymal transition (EMT). Breast Cancer Res Treat 2010, 124:317-326.
• [19]Rhodes LV, Antoon JW, Muir SE, Elliott S, Beckman BS, Burow ME: Effects of human mesenchymal stem cells on ER-positive human breast carcinoma cells mediated through ER-SDF-1/CXCR4 crosstalk. Mol Cancer 2010, 9:295. BioMed Central Full Text
• [20]Rhodes LV, Muir SE, Elliott S, Guillot LM, Antoon JW, Penfornis P, Tilghman SL, Salvo VA, Fonseca JP, Lacey MR, et al.: Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence. Breast Cancer Res Treat 2010, 121:293-300.
• [21]Greco SJ, Patel SA, Bryan M, Pliner LF, Banerjee D, Rameshwar P: AMD3100-mediated production of interleukin-1 from mesenchymal stem cells is key to chemosensitivity of breast cancer cells. Am J Cancer Res 2011, 1:701-715.
• [22]Roodhart JM, Daenen LG, Stigter EC, Prins HJ, Gerrits J, Houthuijzen JM, Gerritsen MG, Schipper HS, Backer MJ, van Amersfoort M, et al.: Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell 2011, 20:370-383.
• [23]Kucerova L, Kovacovicova M, Polak S, Bohac M, Fedeles J, Palencar D, Matuskova M: Interaction of human adipose tissue-derived mesenchymal stromal cells with breast cancer cells. Neoplasma 2011, 58:361-370.
• [24]Klopp AH, Lacerda L, Gupta A, Debeb BG, Solley T, Li L, Spaeth E, Xu W, Zhang X, Lewis MT, et al.: Mesenchymal stem cells promote mammosphere formation and decrease E-cadherin in normal and malignant breast cells. PLoS One 2010, 5:e12180.
• [25]Sullivan NJ, Sasser AK, Axel AE, Vesuna F, Raman V, Ramirez N, Oberyszyn TM, Hall BM: Interleukin-6 induces an epithelial-mesenchymal transition phenotype in human breast cancer cells. Oncogene 2009, 28:2940-2947.
• [26]Zhu W, Huang L, Li Y, Zhang X, Gu J, Yan Y, Xu X, Wang M, Qian H, Xu W: Exosomes derived from human bone marrow mesenchymal stem cells promote tumor growth in vivo. Cancer Lett 2012, 315:28-37.
• [27]Kidd S, Spaeth E, Klopp A, Andreeff M, Hall B, Marini FC: The (in) auspicious role of mesenchymal stromal cells in cancer: be it friend or foe. Cytotherapy 2008, 10:657-667.
• [28]Klopp AH, Gupta A, Spaeth E, Andreeff M, Marini F 3rd: Concise review: dissecting a discrepancy in the literature: do mesenchymal stem cells support or suppress tumor growth? Stem Cells 2011, 29:11-19.
• [29]Kucerova L, Matuskova M, Hlubinova K, Altanerova V, Altaner C: Tumor cell behaviour modulation by mesenchymal stromal cells. Mol Cancer 2010, 9:129. BioMed Central Full Text
• [30]Anton K, Glod J: Targeting the tumor stroma in cancer therapy. Curr Pharm Biotechnol 2009, 10:185-191.
• [31]Hiscox S, Barrett-Lee P, Nicholson RI: Therapeutic targeting of tumor-stroma interactions. Expert Opin Ther Targets 2011, 15:609-621.
• [32]Cihova M, Altanerova V, Altaner C: Stem cell based cancer gene therapy. Mol Pharm 2011, 8:1480-1487.
• [33]Kucerova L, Poturnajova M, Tyciakova S, Matuskova M: Increased proliferation and chemosensitivity of human mesenchymal stromal cells expressing fusion yeast cytosine deaminase. Stem Cell Res 2012, 8:247-258.
• [34]Kucerova L, Altanerova V, Matuskova M, Tyciakova S, Altaner C: Adipose tissue-derived human mesenchymal stem cells mediated prodrug cancer gene therapy. Cancer Res 2007, 67:6304-6313.
• [35]Ansieau S: EMT in breast cancer stem cell generation. Cancer Lett 2013, 338:63-68.
• [36]Ungefroren H, Sebens S, Seidl D, Lehnert H, Hass R: Interaction of tumor cells with the microenvironment. Cell Commun Signal 2011, 9:18. BioMed Central Full Text
• [37]Moharita AL, Taborga M, Corcoran KE, Bryan M, Patel PS, Rameshwar P: SDF-1alpha regulation in breast cancer cells contacting bone marrow stroma is critical for normal hematopoiesis. Blood 2006, 108:3245-3252.
• [38]Cabioglu N, Summy J, Miller C, Parikh NU, Sahin AA, Tuzlali S, Pumiglia K, Gallick GE, Price JE: CXCL-12/stromal cell-derived factor-1alpha transactivates HER2-neu in breast cancer cells by a novel pathway involving Src kinase activation. Cancer Res 2005, 65:6493-6497.
• [39]Serrati S, Margheri F, Fibbi G, Di Cara G, Minafra L, Pucci-Minafra I, Liotta F, Annunziato F, Pucci M, Del Rosso M: Endothelial cells and normal breast epithelial cells enhance invasion of breast carcinoma cells by CXCR-4-dependent up-regulation of urokinase-type plasminogen activator receptor (uPAR, CD87) expression. J Pathol 2008, 214:545-554.
• [40]Hanahan D, Weinberg RA: Hallmarks of cancer: the next generation. Cell 2011, 144:646-674.
• [41]Casiraghi F, Remuzzi G, Abbate M, Perico N: Multipotent Mesenchymal Stromal Cell Therapy and Risk of Malignancies. Stem Cell Rev 2012,  .
• [42]Kim J, Escalante LE, Dollar BA, Hanson SE, Hematti P: Comparison of Breast and Abdominal Adipose Tissue Mesenchymal Stromal/Stem Cells in Support of Proliferation of Breast Cancer Cells. Cancer Invest 2013,  .
• [43]Yan XL, Fu CJ, Chen L, Qin JH, Zeng Q, Yuan HF, Nan X, Chen HX, Zhou JN, Lin YL, et al.: Mesenchymal stem cells from primary breast cancer tissue promote cancer proliferation and enhance mammosphere formation partially via EGF/EGFR/Akt pathway. Breast Cancer Res Treat 2012, 132:153-164.
• [44]Senst C, Nazari-Shafti T, Kruger S, Honer Zu Bentrup K, Dupin CL, Chaffin AE, Srivastav SK, Worner PM, Abdel-Mageed AB, Alt EU, Izadpanah R: Prospective dual role of mesenchymal stem cells in breast tumor microenvironment. Breast Cancer Res Treat 2013, 137:69-79.
• [45]Sarrio D, Franklin CK, Mackay A, Reis-Filho JS, Isacke CM: Epithelial and mesenchymal subpopulations within normal basal breast cell lines exhibit distinct stem cell/progenitor properties. Stem Cells 2012, 30:292-303.
• [46]Weigand M, Hantel P, Kreienberg R, Waltenberger J: Autocrine vascular endothelial growth factor signalling in breast cancer. Evidence from cell lines and primary breast cancer cultures in vitro. Angiogenesis 2005, 8:197-204.
• [47]El-Haibi CP, Bell GW, Zhang J, Collmann AY, Wood D, Scherber CM, Csizmadia E, Mariani O, Zhu C, Campagne A, et al.: Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy. Proc Natl Acad Sci U S A 2012, 109:17460-17465.
• [48]Kucerova L, Matuskova M, Hlubinova K, Bohovic R, Feketeova L, Janega P, Babal P, Poturnajova M: Bystander cytotoxicity in human medullary thyroid carcinoma cells mediated by fusion yeast cytosine deaminase and 5-fluorocytosine. Cancer Lett 2011, 311:101-112.
• [49]Zhu Y, Sun Z, Han Q, Liao L, Wang J, Bian C, Li J, Yan X, Liu Y, Shao C, Zhao RC: Human mesenchymal stem cells inhibit cancer cell proliferation by secreting DKK-1. Leukemia 2009, 23:925-933.
• [50]Lu YR, Yuan Y, Wang XJ, Wei LL, Chen YN, Cong C, Li SF, Long D, Tan WD, Mao YQ, et al.: The growth inhibitory effect of mesenchymal stem cells on tumor cells in vitro and in vivo. Cancer Biol Ther 2008, 7:245-251.
• [51]Spaeth E, Klopp A, Dembinski J, Andreeff M, Marini F: Inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells. Gene Ther 2008, 15:730-738.
• [52]Mantovani A, Allavena P, Sica A, Balkwill F: Cancer-related inflammation. Nature 2008, 454:436-444.
• [53]Chaturvedi P, Gilkes DM, Wong CC, Luo W, Zhang H, Wei H, Takano N, Schito L, Levchenko A, Semenza GL: Hypoxia-inducible factor-dependent breast cancer-mesenchymal stem cell bidirectional signaling promotes metastasis. J Clin Invest 2013, 123:189-205.
• [54]Dittmer A, Fuchs A, Oerlecke I, Leyh B, Kaiser S, Martens JW, Lutzkendorf J, Muller L, Dittmer J: Mesenchymal stem cells and carcinoma-associated fibroblasts sensitize breast cancer cells in 3D cultures to kinase inhibitors. Int J Oncol 2011, 39:689-696.
• [55]Houthuijzen JM, Daenen LG, Roodhart JM, Voest EE: The role of mesenchymal stem cells in anti-cancer drug resistance and tumour progression. Br J Cancer 2012, 106:1901-1906.
• [56]Zimmerlin L, Park TS, Zambidis ET, Donnenberg VS, Donnenberg AD: Mesenchymal stem cell secretome and regenerative therapy after cancer. Biochimie 2013,  .