Secreted Soluble Factors from Tumor-Activated Mesenchymal Stromal Cells Confer Platinum Chemoresistance to Ovarian Cancer Cells

Overview

Journal Int J Mol Sci

Publisher MDPI

Specialties Biochemistry
Chemistry
Molecular Biology

Date 2023 May 13

PMID 37175439

Authors

Yifat Koren Carmi

Hazem Khamaisi

Rina Adawi

Eden Noyman

Jacob Gopas

Jamal Mahajna

Affiliations

Soon will be listed here.

Abstract

Ovarian cancer (OC) ranks as the second most common type of gynecological malignancy, has poor survival rates, and is frequently diagnosed at an advanced stage. Platinum-based chemotherapy, such as carboplatin, represents the standard-of-care for OC. However, toxicity and acquired resistance to therapy have proven challenging for the treatment of patients. Chemoresistance, a principal obstacle to durable response in OC patients, is attributed to alterations within the cancer cells, and it can also be mediated by the tumor microenvironment (TME). In this study, we report that conditioned medium (CM) derived from murine and human stromal cells, MS-5 and HS-5, respectively, and tumor-activated HS-5, was active in conferring platinum chemoresistance to OC cells. Moreover, CM derived from differentiated murine pre-adipocyte (3T3-L1), but not undifferentiated pre-adipocyte cells, confers platinum chemoresistance to OC cells. Interestingly, CM derived from tumor-activated HS-5 was more effective in conferring chemoresistance than was CM derived from HS-5 cells. Various OC cells exhibit variable sensitivity to CM activity. Exploring CM content revealed the enrichment of a number of soluble factors in the tumor-activated HS-5, such as soluble uPAR (SuPAR), IL-6, and hepatocyte growth factor (HGF). FDA-approved JAK inhibitors were mildly effective in restoring platinum sensitivity in two of the three OC cell lines in the presence of CM. Moreover, Crizotinib, an ALK and c-MET inhibitor, in combination with platinum, blocked HGF's ability to promote platinum resistance and to restore platinum sensitivity to OC cells. Finally, exposure to 2-hydroxyestardiol (2HE2) was effective in restoring platinum sensitivity to OC cells exposed to CM. Our results showed the significance of soluble factors found in TME in promoting platinum chemoresistance and the potential of combination therapy to restore chemosensitivity to OC cells.

Citing Articles

Adipocyte Precursor-Derived NRG1 Promotes Resistance to FGFR Inhibition in Urothelial Carcinoma.

Hosni S, Kilian V, Klumper N, Gabbia D, Sieckmann K, Corvino D Cancer Res. 2024; 84(5):725-740.

PMID: 38175774 PMC: 10911805. DOI: 10.1158/0008-5472.CAN-23-1398.

References

Asschert J, Vellenga E, Ruiters M, De Vries E . Regulation of spontaneous and TNF/IFN-induced IL-6 expression in two human ovarian-carcinoma cell lines. Int J Cancer. 1999; 82(2):244-9. DOI: 10.1002/(sici)1097-0215(19990719)82:2<244::aid-ijc15>3.0.co;2-n. View

Raghav K, Gonzalez-Angulo A, Blumenschein Jr G . Role of HGF/MET axis in resistance of lung cancer to contemporary management. Transl Lung Cancer Res. 2015; 1(3):179-93. PMC: 4367559. DOI: 10.3978/j.issn.2218-6751.2012.09.04. View

Nakamura T, Nishizawa T, Hagiya M, Seki T, Shimonishi M, Sugimura A . Molecular cloning and expression of human hepatocyte growth factor. Nature. 1989; 342(6248):440-3. DOI: 10.1038/342440a0. View

Yousefi H, Momeny M, Ghaffari S, Parsanejad N, Poursheikhani A, Javadikooshesh S . IL-6/IL-6R pathway is a therapeutic target in chemoresistant ovarian cancer. Tumori. 2018; 105(1):84-91. DOI: 10.1177/0300891618784790. View

Lane D, Matte I, Rancourt C, Piche A . Prognostic significance of IL-6 and IL-8 ascites levels in ovarian cancer patients. BMC Cancer. 2011; 11:210. PMC: 3118896. DOI: 10.1186/1471-2407-11-210. View

Carmi Y, Mahmoud H, Khamaisi H, Adawi R, Gopas J, Mahajna J . Flavonoids Restore Platinum Drug Sensitivity to Ovarian Carcinoma Cells in a Phospho-ERK1/2-Dependent Fashion. Int J Mol Sci. 2020; 21(18). PMC: 7555577. DOI: 10.3390/ijms21186533. View

Xuan X, Tian C, Zhao M, Sun Y, Huang C . Mesenchymal stem cells in cancer progression and anticancer therapeutic resistance. Cancer Cell Int. 2021; 21(1):595. PMC: 8570012. DOI: 10.1186/s12935-021-02300-4. View

McLean K, Tan L, Bolland D, Coffman L, Peterson L, Talpaz M . Leukemia inhibitory factor functions in parallel with interleukin-6 to promote ovarian cancer growth. Oncogene. 2018; 38(9):1576-1584. PMC: 6374186. DOI: 10.1038/s41388-018-0523-6. View

Yun C, Lee S . The Roles of Autophagy in Cancer. Int J Mol Sci. 2018; 19(11). PMC: 6274804. DOI: 10.3390/ijms19113466. View

10.

Li H, Yang P, Wang J, Zhang J, Ma Q, Jiang Y . HLF regulates ferroptosis, development and chemoresistance of triple-negative breast cancer by activating tumor cell-macrophage crosstalk. J Hematol Oncol. 2022; 15(1):2. PMC: 8740349. DOI: 10.1186/s13045-021-01223-x. View

11.

Cohen S, Lippard S . Cisplatin: from DNA damage to cancer chemotherapy. Prog Nucleic Acid Res Mol Biol. 2001; 67:93-130. DOI: 10.1016/s0079-6603(01)67026-0. View

12.

Wang N, Wang S, Wang X, Zheng Y, Yang B, Zhang J . Research trends in pharmacological modulation of tumor-associated macrophages. Clin Transl Med. 2021; 11(1):e288. PMC: 7805405. DOI: 10.1002/ctm2.288. View

13.

OHare T, Shakespeare W, Zhu X, Eide C, Rivera V, Wang F . AP24534, a pan-BCR-ABL inhibitor for chronic myeloid leukemia, potently inhibits the T315I mutant and overcomes mutation-based resistance. Cancer Cell. 2009; 16(5):401-12. PMC: 2804470. DOI: 10.1016/j.ccr.2009.09.028. View

14.

Blomberg K, Hansen T, Brasen C, Madsen J, Jensen L, Thomsen C . The Soluble Urokinase-Type Plasminogen Activator Receptor as a Biomarker for Survival and Early Treatment Effect in Metastatic Colorectal Cancer. Cancers (Basel). 2021; 13(20). PMC: 8534079. DOI: 10.3390/cancers13205100. View

15.

Stuart K, Riordan S, Lidder S, Crostella L, Williams R, Skouteris G . Hepatocyte growth factor/scatter factor-induced intracellular signalling. Int J Exp Pathol. 2000; 81(1):17-30. PMC: 2517792. DOI: 10.1046/j.1365-2613.2000.00138.x. View

16.

Jung J, Shih I, Park J, Gerry E, Kim T, Ayhan A . Ovarian Cancer Chemoresistance Relies on the Stem Cell Reprogramming Factor PBX1. Cancer Res. 2016; 76(21):6351-6361. PMC: 7375390. DOI: 10.1158/0008-5472.CAN-16-0980. View

17.

Zou H, Li Q, Lee J, Arango M, McDonnell S, Yamazaki S . An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms. Cancer Res. 2007; 67(9):4408-17. DOI: 10.1158/0008-5472.CAN-06-4443. View

18.

Zou M, Zhang X, Xu C . IL6-induced metastasis modulators p-STAT3, MMP-2 and MMP-9 are targets of 3,3'-diindolylmethane in ovarian cancer cells. Cell Oncol (Dordr). 2015; 39(1):47-57. DOI: 10.1007/s13402-015-0251-7. View

19.

Deying W, Feng G, Shumei L, Hui Z, Ming L, Hongqing W . CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Biosci Rep. 2017; 37(2). PMC: 5469328. DOI: 10.1042/BSR20160470. View

20.

Huang X, Xie F, Hou L, Chen X, Ou R, Yu J . Crizotinib synergizes with cisplatin in preclinical models of ovarian cancer. Am J Transl Res. 2017; 9(4):1667-1679. PMC: 5411916. View