{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T00:59:18Z","timestamp":1792803558618,"version":"4.5.0"},"reference-count":75,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T00:00:00Z","timestamp":1595808000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000005","name":"U.S. Department of Defense","doi-asserted-by":"publisher","award":["W81XWH-13-1-0134, W81XWH-16-1-0426, W81XWH-18-0346"],"award-info":[{"award-number":["W81XWH-13-1-0134, W81XWH-16-1-0426, W81XWH-18-0346"]}],"id":[{"id":"10.13039\/100000005","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Within the ovarian cancer tumor microenvironment, cancer stem-like cells (CSC) interact with carcinoma associated mesenchymal stem\/stromal cells (CA-MSC) through multiple secreted cytokines and growth factors. These paracrine interactions have been revealed to cause enrichment of CSC and their chemoprotection; however, it is still not known if platelet-derived growth factor (PDGF) signaling is involved in facilitating these responses. In order to probe this undiscovered bidirectional communication, we created a model of ovarian malignant ascites in the three-dimensional (3D) hanging drop heterospheroid array, with CSC and CA-MSC. We hypothesized that PDGF secretion by CA-MSC increases self-renewal, migration, epithelial to mesenchymal transition (EMT) and chemoresistance in ovarian CSC. Our results indicate that PDGF signaling in the CSC-MSC heterospheroids significantly increased stemness, metastatic potential and chemoresistance of CSC. Knockdown of PDGFB in MSC resulted in abrogation of these phenotypes in the heterospheroids. Our studies also reveal a cross-talk between PDGF and Hedgehog signaling in ovarian cancer. Overall, our data suggest that when the stromal signaling via PDGF to ovarian CSC is blocked in addition to chemotherapy pressure, the tumor cells are significantly more sensitive to chemotherapy. Our results emphasize the importance of disrupting the signals from the microenvironment to the tumor cells, in order to improve response rates. These findings may lead to the development of combination therapies targeting stromal signaling (such as PDGF and Hedgehog) that can abrogate the tumorigenic, metastatic and platinum resistant phenotypes of ovarian CSC through additional investigations.<\/jats:p>","DOI":"10.3390\/cancers12082063","type":"journal-article","created":{"date-parts":[[2020,7,27]],"date-time":"2020-07-27T04:39:50Z","timestamp":1595824790000},"page":"2063","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":72,"title":["Carcinoma-Associated Mesenchymal Stem Cells Promote Chemoresistance in Ovarian Cancer Stem Cells via PDGF Signaling"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4631-7762","authenticated-orcid":false,"given":"Shreya","family":"Raghavan","sequence":"first","affiliation":[{"name":"Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6636-2798","authenticated-orcid":false,"given":"Catherine S.","family":"Snyder","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anni","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7833-1967","authenticated-orcid":false,"given":"Karen","family":"McLean","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Michigan Medicine, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dmitriy","family":"Zamarin","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Medical Oncology and Immunotherapeutics, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronald J.","family":"Buckanovich","sequence":"additional","affiliation":[{"name":"Director of Ovarian Cancer Research, Magee Womens Research Institute, University of Pittsburgh, Pittsburgh, PA 15260, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5967-6425","authenticated-orcid":false,"given":"Geeta","family":"Mehta","sequence":"additional","affiliation":[{"name":"Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Department of Macromolecular Sciences and Engineering, University of Michigan, Ann Arbor, MI 48109, USA"},{"name":"Precision Health, University of Michigan, Ann Arbor, MI 48109, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"22832","DOI":"10.18632\/oncotarget.25126","article-title":"Role of tumor microenvironment in ovarian cancer pathobiology","volume":"9","author":"Ghoneum","year":"2018","journal-title":"Oncotarget"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"7","DOI":"10.3322\/caac.21551","article-title":"Cancer statistics, 2019","volume":"69","author":"Siegel","year":"2019","journal-title":"CA Cancer J. Clin."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1016\/j.biocel.2018.12.010","article-title":"Ovarian cancer stem cells: What progress have we made?","volume":"107","author":"Pandya","year":"2019","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"64","DOI":"10.1186\/s12943-017-0638-3","article-title":"Ovarian cancer stem cells: Still an elusive entity?","volume":"16","author":"Lupia","year":"2017","journal-title":"Mol. Cancer"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Stack, M.S., Nephew, K.P., Burdette, J.E., and Mitra, A.K. (2018). The Tumor Microenvironment of High Grade Serous Ovarian Cancer. Cancers, 11.","DOI":"10.3390\/cancers11010021"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1158\/1078-0432.CCR-11-2188","article-title":"Stem cell pathways contribute to clinical chemoresistance in ovarian cancer","volume":"18","author":"Steg","year":"2012","journal-title":"Clin. Cancer Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1007\/s13238-017-0466-7","article-title":"Revisiting ovarian cancer microenvironment: A friend or a foe?","volume":"9","author":"Zhang","year":"2018","journal-title":"Protein Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"3991","DOI":"10.1158\/0008-5472.CAN-10-3175","article-title":"Aldehyde dehydrogenase in combination with CD133 defines angiogenic ovarian cancer stem cells that portend poor patient survival","volume":"71","author":"Silva","year":"2011","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3186","DOI":"10.1158\/1535-7163.MCT-10-0563","article-title":"Targeting aldehyde dehydrogenase cancer stem cells in ovarian cancer","volume":"9","author":"Landen","year":"2010","journal-title":"Mol. Cancer Ther."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1038\/modpathol.2011.170","article-title":"CD133 expression associated with poor prognosis in ovarian cancer","volume":"25","author":"Zhang","year":"2012","journal-title":"Mod. Pathol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"E6882","DOI":"10.1073\/pnas.1507899112","article-title":"Identifying an ovarian cancer cell hierarchy regulated by bone morphogenetic protein 2","volume":"112","author":"Choi","year":"2015","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"2875","DOI":"10.1002\/stem.236","article-title":"CD133 expression defines a tumor initiating cell population in primary human ovarian cancer","volume":"27","author":"Curley","year":"2009","journal-title":"Stem Cells"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1016\/j.ygyno.2016.03.022","article-title":"Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy","volume":"142","author":"Sharrow","year":"2016","journal-title":"Gynecol. Oncol."},{"key":"ref_14","first-page":"3080","article-title":"Prognostic value of cancer stem cell marker CD133 in ovarian cancer: A meta-analysis","volume":"8","author":"Zhou","year":"2015","journal-title":"Int. J. Clin. Exp. Med."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1038\/onc.2008.374","article-title":"Epigenetic regulation of CD133 and tumorigenicity of CD133+ ovarian cancer cells","volume":"28","author":"Baba","year":"2009","journal-title":"Oncogene"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1002\/ijc.25967","article-title":"Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells","volume":"130","author":"Kryczek","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"157","DOI":"10.2174\/187152010790909272","article-title":"Targeting ovarian cancer-initiating cells","volume":"10","author":"Murphy","year":"2010","journal-title":"Anticancer Agents Med. Chem."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"61","DOI":"10.1007\/978-1-4939-7401-6_6","article-title":"Self-Renewal and CSCs In Vitro Enrichment: Growth as Floating Spheres","volume":"1692","author":"Mehta","year":"2018","journal-title":"Methods Mol. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"6934","DOI":"10.1158\/1078-0432.CCR-17-0133","article-title":"Personalized Medicine\u2013Based Approach to Model Patterns of Chemoresistance and Tumor Recurrence Using Ovarian Cancer Stem Cell Spheroids","volume":"23","author":"Raghavan","year":"2017","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1186\/s40425-019-0666-1","article-title":"Ovarian cancer stem cells and macrophages reciprocally interact through the WNT pathway to promote pro-tumoral and malignant phenotypes in 3D engineered microenvironments","volume":"7","author":"Raghavan","year":"2019","journal-title":"J. Immunother. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1016\/j.neo.2019.06.005","article-title":"Engineered 3D Model of Cancer Stem Cell Enrichment and Chemoresistance","volume":"21","author":"Mehta","year":"2019","journal-title":"Neoplasia"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"6916","DOI":"10.18632\/oncotarget.6870","article-title":"Human carcinoma-associated mesenchymal stem cells promote ovarian cancer chemotherapy resistance via a BMP4\/HH signaling loop","volume":"7","author":"Coffman","year":"2016","journal-title":"Oncotarget"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1038\/nature06188","article-title":"Mesenchymal stem cells within tumour stroma promote breast cancer metastasis","volume":"449","author":"Karnoub","year":"2007","journal-title":"Nature"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1002\/path.4889","article-title":"Mesothelial-to-mesenchymal transition as a possible therapeutic target in peritoneal metastasis of ovarian cancer","volume":"242","author":"Yeung","year":"2017","journal-title":"J. Pathol."},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Spaeth, E.L., Dembinski, J.L., Sasser, A.K., Watson, K., Klopp, A., Hall, B., Andreeff, M., and Marini, F. (2009). Mesenchymal Stem Cell Transition to Tumor-Associated Fibroblasts Contributes to Fibrovascular Network Expansion and Tumor Progression. PLoS ONE, 4.","DOI":"10.1371\/journal.pone.0004992"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/j.ygyno.2011.08.005","article-title":"Exosomes from ovarian cancer cells induce adipose tissue-derived mesenchymal stem cells to acquire the physical and functional characteristics of tumor-supporting myofibroblasts","volume":"123","author":"Cho","year":"2011","journal-title":"Gynecol. Oncol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1815","DOI":"10.7150\/jca.16116","article-title":"Interleukin-6 from Ovarian Mesenchymal Stem Cells Promotes Proliferation, Sphere and Colony Formation and Tumorigenesis of an Ovarian Cancer Cell Line SKOV3","volume":"7","author":"Ding","year":"2016","journal-title":"J. Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3206","DOI":"10.1172\/JCI45273","article-title":"Human ovarian carcinoma\u2013associated mesenchymal stem cells regulate cancer stem cells and tumorigenesis via altered BMP production","volume":"121","author":"McLean","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"e887","DOI":"10.1038\/cddis.2013.384","article-title":"Microenvironment mesenchymal cells protect ovarian cancer cell lines from apoptosis by inhibiting XIAP inactivation","volume":"4","author":"Castells","year":"2013","journal-title":"Cell Death Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1655","DOI":"10.2147\/OTT.S129502","article-title":"Human omental adipose-derived mesenchymal stem cell-conditioned medium alters the proteomic profile of epithelial ovarian cancer cell lines in vitro","volume":"10","author":"Zhang","year":"2017","journal-title":"Oncotargets Ther."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1182\/blood-2007-07-103697","article-title":"PDGF, TGF-\u03b2, and FGF signaling is important for differentiation and growth of mesenchymal stem cells (MSCs): Transcriptional profiling can identify markers and signaling pathways important in differentiation of MSCs into adipogenic, chondrogenic, and osteogenic lineages","volume":"112","author":"Ng","year":"2008","journal-title":"Blood"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1631","DOI":"10.5966\/sctm.2015-0360","article-title":"Platelet-Derived Growth Factor-BB Protects Mesenchymal Stem Cells (MSCs) Derived From Immune Thrombocytopenia Patients Against Apoptosis and Senescence and Maintains MSC-Mediated Immunosuppression","volume":"5","author":"Zhang","year":"2016","journal-title":"Stem Cells Transl. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.ygyno.2003.12.041","article-title":"Expression of platelet-derived growth factor and activated receptor in clinical specimens of epithelial ovarian cancer and ovarian carcinoma cell lines","volume":"93","author":"Apte","year":"2004","journal-title":"Gynecol. Oncol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1006\/gyno.1998.5121","article-title":"The Effects of Platelet-Derived Growth Factor and Receptor on Normal and Neoplastic Human Ovarian Surface Epithelium","volume":"71","author":"Dabrow","year":"1998","journal-title":"Gynecol. Oncol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/0165-4608(94)90183-X","article-title":"Human ovarian tumors of epithelial origin express PDGF in vitro and in vivo","volume":"73","author":"Versnel","year":"1994","journal-title":"Cancer Genet. Cytogenet."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"232","DOI":"10.1159\/000363656","article-title":"Nilotinib in Combination with Carboplatin and Paclitaxel Is a Candidate for Ovarian Cancer Treatment","volume":"87","author":"Weigel","year":"2014","journal-title":"Oncology"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1038\/s41389-018-0059-1","article-title":"Platelet-derived growth factor receptor-\u03b1 and -\u03b2 promote cancer stem cell phenotypes in sarcomas","volume":"7","author":"Chang","year":"2018","journal-title":"Oncogenesis"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"963","DOI":"10.1097\/JTO.0b013e3181834f52","article-title":"Prognostic Impact of Platelet-Derived Growth Factors in Non-small Cell Lung Cancer Tumor and Stromal Cells","volume":"3","author":"Donnem","year":"2008","journal-title":"J. Thorac. Oncol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1002\/cbf.3120","article-title":"Platelet-derived growth factor (PDGF) signalling in cancer: Rapidly emerging signalling landscape","volume":"33","author":"Farooqi","year":"2015","journal-title":"Cell Biochem. Funct."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1835","DOI":"10.1007\/s00432-014-1723-2","article-title":"Gastric cancer-derived MSC-secreted PDGF-DD promotes gastric cancer progression","volume":"140","author":"Huang","year":"2014","journal-title":"J. Cancer Res. Clin. Oncol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"1011","DOI":"10.1158\/0008-5472.CAN-13-1072","article-title":"Oligodendrocyte Progenitor Cells Promote Neovascularization in Glioma by Disrupting the Blood\u2013Brain Barrier","volume":"74","author":"Huang","year":"2014","journal-title":"Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"187","DOI":"10.1016\/j.neuron.2006.06.012","article-title":"PDGFR\u03b1-Positive B Cells Are Neural Stem Cells in the Adult SVZ that Form Glioma-like Growths in Response to Increased PDGF Signaling","volume":"51","author":"Jackson","year":"2006","journal-title":"Neuron"},{"key":"ref_43","doi-asserted-by":"crossref","unstructured":"Pinto, M.P., Dye, W.W., Jacobsen, B.M., and Horwitz, K.B. (2014). Malignant stroma increases luminal breast cancer cell proliferation and angiogenesis through platelet-derived growth factor signaling. BMC Cancer, 14.","DOI":"10.1186\/1471-2407-14-735"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1023","DOI":"10.1002\/ijc.26493","article-title":"Epithelial\u2013mesenchymal transition in breast cancer lines is mediated through PDGF-D released by tissue-resident stem cells","volume":"131","author":"Devarajan","year":"2012","journal-title":"Int. J. Cancer"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2076","DOI":"10.1002\/hep.24588","article-title":"Myofibroblast-derived PDGF-BB Promotes Hedgehog Survival Signaling in Cholangiocarcinoma Cells","volume":"54","author":"Fingas","year":"2011","journal-title":"Hepatology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"3395","DOI":"10.1038\/sj.onc.1210121","article-title":"PDGF essentially links TGF-\u03b2 signaling to nuclear \u03b2-catenin accumulation in hepatocellular carcinoma progression","volume":"26","author":"Fischer","year":"2007","journal-title":"Oncogene"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.1634\/stemcells.2007-1076","article-title":"Platelet-Derived Growth Factor-D Overexpression Contributes to Epithelial-Mesenchymal Transition of PC3 Prostate Cancer Cells","volume":"26","author":"Kong","year":"2008","journal-title":"Stem Cells"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2265","DOI":"10.1093\/annonc\/mds003","article-title":"A phase II trial (AGO 2.11) in platinum-resistant ovarian cancer: A randomized multicenter trial with sunitinib (SU11248) to evaluate dosage, schedule, tolerability, toxicity and effectiveness of a multitargeted receptor tyrosine kinase inhibitor monotherapy","volume":"23","author":"Baumann","year":"2012","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1093\/annonc\/mdq357","article-title":"A phase II study of sunitinib in patients with recurrent epithelial ovarian and primary peritoneal carcinoma: An NCIC Clinical Trials Group Study","volume":"22","author":"Biagi","year":"2011","journal-title":"Ann. Oncol. Off. J. Eur. Soc. Med. Oncol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"2897","DOI":"10.1038\/s41467-018-05220-6","article-title":"Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer","volume":"9","author":"Cazet","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"354","DOI":"10.1093\/jjco\/hyz009","article-title":"Efficacy and safety of sunitinib in Japanese patients with progressive, advanced\/metastatic, well-differentiated, unresectable pancreatic neuroendocrine tumors: Final analyses from a Phase II study","volume":"49","author":"Ito","year":"2019","journal-title":"Jpn. J. Clin. Oncol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1159\/000491999","article-title":"Efficacy and Safety of Sunitinib in Patients with Well-Differentiated Pancreatic Neuroendocrine Tumours","volume":"107","author":"Raymond","year":"2018","journal-title":"Neuroendocrinology"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.phrs.2018.01.021","article-title":"The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders","volume":"129","author":"Roskoski","year":"2018","journal-title":"Pharmacol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"766","DOI":"10.1007\/s10637-017-0454-z","article-title":"Phase I trial of the oral smoothened inhibitor sonidegib in combination with paclitaxel in patients with advanced solid tumors","volume":"35","author":"Stathis","year":"2017","journal-title":"Investig. New Drugs"},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Bregenzer, M.E., Davis, C., Horst, E.N., Mehta, P., Novak, C.M., Raghavan, S., Snyder, C.S., and Mehta, G. (2019). Physiologic Patient Derived 3D Spheroids for Anti-neoplastic Drug Screening to Target Cancer Stem Cells. J. Vis. Exp.","DOI":"10.3791\/59696"},{"key":"ref_56","unstructured":"Papaccio, G., and Desiderio, V. (2018). Self-Renewal and CSCs In Vitro Enrichment: Growth as Floating Spheres. Cancer Stem Cells: Methods and Protocols, Springer."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Raghavan, S., Mehta, P., Horst, E.N., Ward, M.R., Rowley, K.R., and Mehta, G. (2016). Comparative analysis of tumor spheroid generation techniques for differential in vitro drug toxicity. Oncotarget.","DOI":"10.18632\/oncotarget.7659"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.ygyno.2015.04.014","article-title":"Formation of stable small cell number three-dimensional ovarian cancer spheroids using hanging drop arrays for preclinical drug sensitivity assays","volume":"138","author":"Raghavan","year":"2015","journal-title":"Gynecol. Oncol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1158\/1078-0432.CCR-09-1630","article-title":"Aldehyde Dehydrogenase 1\u2013Positive Cancer Stem Cells Mediate Metastasis and Poor Clinical Outcome in Inflammatory Breast Cancer","volume":"16","author":"Ginestier","year":"2010","journal-title":"Clin. Cancer Res."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.canlet.2017.02.026","article-title":"Fibroblast-led cancer cell invasion is activated by epithelial-mesenchymal transition through platelet-derived growth factor BB secretion of lung adenocarcinoma","volume":"395","author":"Neri","year":"2017","journal-title":"Cancer Lett."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"204","DOI":"10.1593\/neo.121726","article-title":"PDGFRB promotes liver metastasis formation of mesenchymal-like colorectal tumor cells","volume":"15","author":"Steller","year":"2013","journal-title":"Neoplasia"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"370","DOI":"10.1016\/j.ccr.2011.08.010","article-title":"Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids","volume":"20","author":"Roodhart","year":"2011","journal-title":"Cancer Cell"},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"438","DOI":"10.18632\/genesandcancer.129","article-title":"Inhibition of the platelet-derived growth factor receptor beta (PDGFRB) using gene silencing, crenolanib besylate, or imatinib mesylate hampers the malignant phenotype of mesothelioma cell lines","volume":"8","author":"Melaiu","year":"2017","journal-title":"Genes Cancer"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"139","DOI":"10.1016\/j.canlet.2005.02.002","article-title":"Platelet-derived growth factor (PDGF) and glial tumorigenesis","volume":"232","author":"Shih","year":"2006","journal-title":"Cancer Lett."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/j.cllc.2011.02.002","article-title":"Immunohistochemical overexpression of platelet-derived growth factor receptor-beta (PDGFR-\u03b2) is associated with PDGFRB gene copy number gain in sarcomatoid non-small cell lung cancer (NSCLC)","volume":"12","author":"Tsao","year":"2011","journal-title":"Clin. Lung Cancer"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"2060","DOI":"10.1038\/sj.onc.1209232","article-title":"Autocrine activation of PDGFR \u03b1 promotes the progression of ovarian cancer","volume":"25","author":"Matei","year":"2006","journal-title":"Oncogene"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1158\/1078-0432.CCR-13-1131","article-title":"The PDGFR\u03b2\u2013AKT Pathway Contributes to CDDP-Acquired Resistance in Testicular Germ Cell Tumors","volume":"20","author":"Juliachs","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1016\/j.canlet.2012.02.035","article-title":"SDF-1\/CXCR4 signaling induces pancreatic cancer cell invasion and epithelial\u2013mesenchymal transition in vitro through non-canonical activation of Hedgehog pathway","volume":"322","author":"Li","year":"2012","journal-title":"Cancer Lett."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"640","DOI":"10.1016\/j.ctrv.2012.11.006","article-title":"Emerging roles of PDGF-D in EMT progression during tumorigenesis","volume":"39","author":"Wu","year":"2013","journal-title":"Cancer Treat. Rev."},{"key":"ref_70","first-page":"73","article-title":"Hedgehog Signaling Pathway as Genetic and Epigenetic Target in Ovarian Tumors","volume":"23","author":"Levanat","year":"2017","journal-title":"Curr. Pharm. Des."},{"key":"ref_71","first-page":"5569","article-title":"Activation of hedgehog signaling and its association with cisplatin resistance in ovarian epithelial tumors","volume":"15","author":"Song","year":"2018","journal-title":"Oncol. Lett."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1093\/carcin\/bgn230","article-title":"Aberrant activation of hedgehog signaling pathway in ovarian cancers: Effect on prognosis, cell invasion and differentiation","volume":"30","author":"Liao","year":"2009","journal-title":"Carcinogenesis"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"2241","DOI":"10.1158\/0008-5472.CAN-07-6350","article-title":"Gli Activity Correlates with Tumor Grade in Platelet-Derived Growth Factor\u2013Induced Gliomas","volume":"68","author":"Becher","year":"2008","journal-title":"Cancer Res."},{"key":"ref_74","doi-asserted-by":"crossref","unstructured":"Charles, N., Ozawa, T., Squatrito, M., Bleau, A.M., Brennan, C.W., Hambardzumyan, D., and Holland, E.C. (2010). Perivascular Nitric Oxide Activates Notch Signaling and Promotes Stem-like Character in PDGF-induced Glioma Cells. Cell Stem Cell, 6.","DOI":"10.1016\/j.stem.2010.01.001"},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"2429","DOI":"10.1182\/blood-2013-06-508689","article-title":"Sonic hedgehog mediates a novel pathway of PDGF-BB\u2013dependent vessel maturation","volume":"123","author":"Yao","year":"2014","journal-title":"Blood"}],"container-title":["Cancers"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/8\/2063\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:51:54Z","timestamp":1760176314000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6694\/12\/8\/2063"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,27]]},"references-count":75,"journal-issue":{"issue":"8","published-online":{"date-parts":[[2020,8]]}},"alternative-id":["cancers12082063"],"URL":"https:\/\/doi.org\/10.3390\/cancers12082063","relation":{},"ISSN":["2072-6694"],"issn-type":[{"value":"2072-6694","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,27]]}}}