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Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells

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Abstract

Purpose

Obesity is as an important risk factor and has been associated with a worse prognosis in at least 13 distinct tumor types. This is partially due to intercellular communication between tumor cells and adipose tissue-derived stem cells (ADSCs), which are increased in obese individuals. As yet, however, little is known about the molecular changes occurring in ADSCs in these conditions. Cervical cancer has a high incidence and mortality rate in women from developing countries, particularly in those with a high body mass index (BMI).

Methods

We analyzed the expression profile of ADSCs co-cultured with cervical cancer cells through massive RNA sequencing followed by evaluation of various functional alterations resulting from the modified transcriptome.

Results

A total of 761 coding and non-coding dysregulated RNAs were identified in ADSCs after co-culture with HeLa cells (validation in CaSki and SiHA cells). Subsequent network analysis showed that these changes were correlated with migration, stemness, DNA repair and cytokine production. Functional experiments revealed a larger ALDHhigh subpopulation and a higher migrative capacity of ADSCs after co-culture with HeLa cells. Interestingly, CXCL3 and its intragenic long-noncoding RNA, lnc-CXCL3, were found to be co-regulated during co-culture. A loss-of-function assay revealed that lnc-CXCL3 acts as a key regulator of CXCL3 expression.

Conclusions

Our results suggest that intercellular communication between ADSCs and cervical cancer cells modifies the RNA expression profile in the former, including that of lncRNAs, which in turn can regulate the expression of diverse chemokines that favor malignancy-associated capacities such as migration.

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Data availability

The data obtained from the sequencing were deposited: SRA data: PRJNA780960.

References

  1. https://www.who.int/es/news-room/fact-sheets/detail/obesity-and-overweight [Internet] Accessed 9 jun 2021

  2. E.E. Calle, R. Kaaks, Overweight, obesity and cancer: Epidemiological evidence and proposed mechanisms. Nat Rev Cancer 4, 579–591 (2004)

    Article  CAS  Google Scholar 

  3. M. Arnold, N. Pandeya, G. Byrnes, P.A.G. Renehan, G.A. Stevens, P.M. Ezzati, J. Ferlay, J.J. Miranda, I. Romieu, R. Dikshit, D. Forman, I. Soerjomataram, Global burden of cancer attributable to high body-mass index in 2012: A population-based study. Lancet Oncol 16, 36–46 (2015)

    Article  Google Scholar 

  4. https://gco.iarc.fr/causes/obesity/tools-pie. https://gco.iarc.fr/causes/obesity/tools-pie [Internet] Accessed 9 jun 2021

  5. B. Lauby-Secretan, C. Scoccianti, D. Loomis, Y. Grosse, F. Bianchini, K. Straif, Body fatness and Cancer--viewpoint of the IARC working group. N Engl J Med 375, 794–798 (2016)

    Article  Google Scholar 

  6. R.C.M. van Kruijsdijk, E. van der Wall, F.L.J. Visseren, Obesity and cancer: The role of dysfunctional adipose tissue. Cancer Epidemiol Biomark Prev 18, 2569–2578 (2009)

    Article  Google Scholar 

  7. S.D. Hursting, N.P. Nunez, L. Varticovski, C. Vinson, The obesity-cancer link: Lessons learned from a fatless mouse. Cancer Res 67, 2391–2393 (2007)

    Article  CAS  Google Scholar 

  8. M.J. Khandekar, P. Cohen, B.M. Spiegelman, Molecular mechanisms of cancer development in obesity. Nat Rev Cancer 11, 886–895 (2011)

    Article  CAS  Google Scholar 

  9. J. Park, T.S. Morley, M. Kim, D.J. Clegg, P.E. Scherer, Obesity and cancer-mechanisms underlying tumour progression and recurrence. Nat Rev Endocrinol 10, 455–465 (2014)

    Article  CAS  Google Scholar 

  10. B.A. Bunnell, M. Flaat, C. Gagliardi, B. Patel, C. Ripoll, Adipose-derived stem cells: Isolation, expansion and differentiation. Methods 45, 115–120 (2008)

    Article  CAS  Google Scholar 

  11. G. Lazennec, P.Y.P. Lam, Recent discoveries concerning the tumor - mesenchymal stem cell interactions. Biochim Biophys Acta 1866, 290–299 (2016)

    PubMed  Google Scholar 

  12. C. Senst, T. Nazari-Shafti, S. Kruger, K.H.Z. Bentrup, C.L. Dupin, A.E. Chaffin, S.K. Srivastav, P.M. Worner, A.B. Abdel-Mageed, E.U. Alt, R. Izadpanah, Prospective dual role of mesenchymal stem cells in breast tumor microenvironment. Breast Cancer Res Treat 137, 69–79 (2013)

    Article  CAS  Google Scholar 

  13. Y. Zhang, A. Daquinag, D.O. Traktuev, F. Amaya-Manzanares, P.J. Simmons, K.L. March, R. Pasqualini, W. Arap, M.G. Kolonin, White adipose tissue cells are recruited by experimental tumors and promote cancer progression in mouse models. Cancer Res 69, 5259–5266 (2009)

    Article  CAS  Google Scholar 

  14. Y. Zhang, C.F. Bellows, M.G. Kolonin, Adipose tissue-derived progenitor cells and cancer. World J Stem Cells 2, 103–113 (2010)

    Article  Google Scholar 

  15. B.-C. Zhao, B. Zhao, J.-G. Han, H.-C. Ma, Z.-J. Wang, Adipose-derived stem cells promote gastric cancer cell growth, migration and invasion through SDF-1/CXCR4 axis. Hepatogastroenterology 57, 1382–1389 (2010)

    CAS  PubMed  Google Scholar 

  16. G. Lin, R. Yang, L. Banie, G. Wang, H. Ning, L.-C. Li, T.F. Lue, C.-S. Lin, Effects of transplantation of adipose tissue-derived stem cells on prostate tumor. Prostate 70, 1066–1073 (2010)

    Article  Google Scholar 

  17. The global cancer observatory https://gco.iarc.fr/today/data/factsheets/populations/484-mexico-fact-sheets.pdf [Internet] Accessed 9 jun 2021

  18. P. A. Zuk, M. Zhu, H. Mizuno, J. Huang, J. W. Futrell, A. J. Katz, P. Benhaim, H. P. Lorenz, M.H, Hedrick, Multilineage cells from human adipose tissue: implications for cell-based therapies. Tissue Eng 7, 211–228 (2001)

  19. C.C. Liang, A.Y. Park, J.L. Guan, In vitro scratch assay: A convenient and inexpensive method for analysis of cell migration in vitro. Nat Protoc 2, 329–333 (2007)

    Article  CAS  Google Scholar 

  20. P.-J. Volders, J. Anckaert, K. Verheggen, J. Nuytens, L. Martens, P. Mestdagh, J. Vandesompele, LNCipedia 5: Towards a reference set of human long non-coding RNAs. Nucleic Acids Res 47, D135–D139 (2019)

    Article  CAS  Google Scholar 

  21. M. Dominici, K. Le Blanc, I. Mueller, I. Slaper-Cortenbach, F.C. Marini, D.S. Krause, R.J. Deans, A. Keating, D.J. Prockop, E.M. Horwitz, Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement Cytotherapy 8, 315–317 (2006)

    CAS  PubMed  Google Scholar 

  22. D. Hanahan, L.M. Coussens, Accessories to the crime: Functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012)

    Article  CAS  Google Scholar 

  23. H. Itoh, S. Nishikawa, T. Haraguchi, Y. Arikawa, S. Eto, M. Hiyama, T. Iseri, Y. Itoh, M. Nakaichi, Y. Sakai, K. Tani, Y. Taura, K. Itamoto, Aldehyde dehydrogenase activity helps identify a subpopulation of murine adipose-derived stem cells with enhanced adipogenic and osteogenic differentiation potential. World J Stem Cells 9, 179–186 (2017)

  24. V. Tirino, V. Desiderio, F. Paino, A. De Rosa, F. Papaccio, M. La Noce, L. Laino, F. De Francesco, G. Papaccio, Cancer stem cells in solid tumors: An overview and new approaches for their isolation and characterization. FASEB J 27, 13–24 (2013)

    Article  CAS  Google Scholar 

  25. L. Mele, D. Liccardo, V. Tirino, Evaluation and isolation of cancer stem cells using ALDH activity assay. Methods Mol Biol 1692, 43–48 (2018)

  26. C. Tang, B. Li, G. Kang, C. Gao, Z. Li, Zhang, GEPIA: A web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res 45, W98–W102 (2017)

    Article  CAS  Google Scholar 

  27. S. P. Poulos, M. V Dodson, G. J. Hausman, Cell line models for differentiation: Preadipocytes and adipocytes. Exp Biol Med (Maywood) 235, 1185–1193 (2010)

  28. L. Zhou, D. Sheng, D. Wang, W. Ma, Q. Deng, L. Deng, S. Liu, Identification of cancer-type specific expression patterns for active aldehyde dehydrogenase (ALDH) isoforms in ALDEFLUOR assay. Cell Biol Toxicol 35, 161–177 (2019)

    Article  Google Scholar 

  29. S. Puttini, I. Plaisance, L. Barile, E. Cervio, G. Milano, P. Marcato, T. Pedrazzini, G. Vassalli, ALDH1A3 is the key isoform that contributes to aldehyde dehydrogenase activity and affects in vitro proliferation in cardiac atrial appendage progenitor cells. Front Cardiovasc Med 5, 1–15 (2018)

    Article  Google Scholar 

  30. Q. He, C. Wan, G. Li, Concise review: Multipotent mesenchymal stromal cells in blood. Stem Cells 25, 69–77 (2007)

    Article  CAS  Google Scholar 

  31. E. Koellensperger, F. Gramley, F. Preisner, U. Leimer, G. Germann, V. Dexheimer, Alterations of gene expression and protein synthesis in co-cultured adipose tissue-derived stem cells and squamous cell-carcinoma cells: Consequences for clinical applications. Stem Cell Res Ther 5, 65 (2014)

    Article  Google Scholar 

  32. M.L. Liu, S.C. Guo, J.K. Stiles, The emerging role of CXCL10 in cancer (review). Oncol Lett 2, 583–589 (2011)

    Article  CAS  Google Scholar 

  33. E. Sato, J. Fujimoto, T. Tamaya, Expression of interferon-gamma-inducible protein 10 related to angiogenesis in uterine endometrial cancers. Oncology 73, 246–251 (2007)

    Article  CAS  Google Scholar 

  34. H.-T. Chen, M.-J. Lee, C.-H. Chen, S.-C. Chuang, L.-F. Chang, M.-L. Ho, S.-H. Hung, Y.-C. Fu, Y.-H. Wang, H.-I. Wang, G.-J. Wang, L. Kang, J.-K, Proliferation and differentiation potential of human adipose-derived mesenchymal stem cells isolated from elderly patients with osteoporotic fractures. J Cell Mol Med 16, 582–593 (2012)

  35. D. Legzdina, A. Romanauska, S. Nikulshin, T. Kozloyska, U. Berzins, Characterization of senescence of culture-expanded human adipose-derived mesenchymal stem cells. Int J Stem Cells 9, 124–136 (2016)

    Article  CAS  Google Scholar 

  36. S. Liu, C. Ginestier, S.J. Ou, S.G. Clouthier, S.H. Patel, F. Monville, Breast cancer stem cells are regulated by mesenchymal stem cells through cytokine networks. Cancer Res 71, 614–624 (2011)

    Article  CAS  Google Scholar 

  37. H.J. Wei, R. Zeng, J.H. Lu, W.F.T. Lai, W.H. Chen, H.Y. Liu, Y.T. Chang, W.P. Deng, Adipose-derived stem cells promote tumor initiation and accelerate tumor growth by interleukin-6 production. Oncotarget 6, 7713–7726 (2015)

    Article  Google Scholar 

  38. P. Escobar, C. Bouclier, J. Serret, I. Bieche, M. Brigitte, A. Caicedo, E. Sanchez, S. Vacher, M.L. Vignais, P. Bourin, D. Genevieve, F. Molina, C. Jorgensen, G. Lazennec, IL-1β produced by aggressive breast cancer cells is one of the factors that dictate their interactions with mesenchymal stem cells through chemokine production. Oncotarget 6, 29034–29047 (2015)

    Article  Google Scholar 

  39. M. Al-toub, A. Almusa, M. Almajed, M. Al-Nbaheen, M. Kassem, A. Aldahmash, N.M. Alajez, Pleiotropic effects of cancer cells’ secreted factors on human stromal (mesenchymal) stem cells. Stem Cell Res Ther 4, 114 (2013)

    Article  Google Scholar 

  40. Y. Inagaki, T. Oda, T. Kurokawa, R. Miyamoto, Y. Kida, N. Ohkohchi, Abstract 171: Adipose-derived mesenchymal stem cell (ADSC) has the differentiation capacity toward cancer associated fibroblast (CAF) and reproduce the morphology of the clinical tumor stroma. In 105th Annual Meeting of the American Association for Cancer Research. Cancer Res 74, 171 (2014)

  41. M. Deng, Y.P. Gu, Z.J. Liu, Y. Qi, G.E. Ma, N. Kang, Endothelial differentiation of human adipose-derived stem cells on polyglycolic acid/polylactic acid mesh. Stem Cells Int 2015, 350718 (2015)

    Article  Google Scholar 

  42. K. M. Nieman, H. A. Kenny, C. V Penicka, A. Ladanyi, R. Buell-Gutbrod, M. R. Zillhardt, I. L. Romero, M. S. Carey, G. B. Mills, G. S. Hotamisligil, S. D. Yamada, M. E. Peter, K. Gwin, E. Lengyel, Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nat Med 17, 1498–1503 (2011)

  43. B.T. Estes, A.W. Wu, R.W. Storms, F. Guilak, Extended passaging, but not aldehyde dehydrogenase activity, increases the chondrogenic potential of human adipose-derived adult stem cells. J Cell Physiol 209, 987–995 (2006)

    Article  CAS  Google Scholar 

  44. H.-J. Li, F. Reinhardt, H.R. Herschman, R.A. Weinberg, Cancer-stimulated mesenchymal stem cells create a carcinoma stem cell niche via prostaglandin E2 signaling. Cancer Discov 2, 840–855 (2012)

    Article  CAS  Google Scholar 

  45. M. Najar, E. Crompot, L.A. van Grunsven, L. Dolle, L. Lagneaux, Aldehyde dehydrogenase activity in adipose tissue: Isolation and gene expression profile of distinct sub-population of mesenchymal stromal cells. Stem Cell Rev Reports 14, 599–611 (2018)

    Article  CAS  Google Scholar 

  46. M. Gasparetto, S. Sekulovic, C. Brocker, P. Tang, A. Zakaryan, P. Xiang, F. Kuchenbauer, M. Wen, K. Kasaian, M.F. Witty, P. Rosten, Y. Chen, S. Imren, G. Duester, D.C. Thompson, R.K. Humphries, V. Vasiliou, C. Smith, Aldehyde dehydrogenases are regulators of hematopoietic stem cell numbers and B-cell development. Exp Hematol 40, 318–329 (2012)

    Article  CAS  Google Scholar 

  47. M. Petruzzelli, M. Schweiger, R. Schreiber, R. Campos-Olivas, M. Tsoli, J. Allen, M. Swarbrick, S. Rose-John, M. Rincon, G. Robertson, R. Zechner, E.F. Wagner, A switch from white to brown fat increases energy expenditure in cancer-associated cachexia. Cell Metab 20, 433–447 (2014)

    Article  CAS  Google Scholar 

  48. S. Kir, J.P. White, S. Kleiner, L. Kazak, P. Cohen, V.E. Baracos, B.M. Spiegelman, Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia. Nature 513, 100–104 (2014)

    Article  CAS  Google Scholar 

  49. A.S. Antonopoulos, D. Tousoulis, The molecular mechanisms of obesity paradox. Cardiovasc Res 113, 1074–1086 (2017)

    Article  CAS  Google Scholar 

  50. W.Q. Hu, J.R. Alvarez-Dominguez, H.F. Lodish, Regulation of mammalian cell differentiation by long non-coding RNAs. EMBO Rep 13, 971–983 (2012)

    Article  CAS  Google Scholar 

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Acknowledgements

This work was part of the PhD thesis of Marcela Angelica De la Fuente Hernandez (CVU: 441075) from the Programa de Doctorado en Ciencias Biológicas, Universidad Nacional Autónoma de México (UNAM). The work was supported by a Consejo Nacional de Ciencia y Tecnologia (CONACyT) fellowship (Registry number 270150). We thank Dr. Alfredo Mendoza for his help in transcriptome sequencing (Unit of Sequencing Genomics, Instituto Nacional de Medicina Genomica, Mexico City), M.C. Linda Nelly Patiño for her help in the cytometry experiments (Unit of Citometry, Instituto Nacional de Medicina Genómica, Mexico City), M.C. Miguel Angel Sarabia Sanchez for his help in the cytometry experiments in the Laboratorio Nacional de Citometría de Flujo (LabNalCit), Mexico City and Dr. Daniel Díaz for his kind assistance in proofreading this manuscript.

Funding

Marcela Angelica De la Fuente Hernandez is a doctoral student from Programa de Doctorado en Ciencias Biologicas, Universidad Nacional Autonoma de México (UNAM) and received a fellowship 270150 from CONACyT. This work was supported by grant A1-S-33543 CONACyT to Vilma Maldonado.

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Authors and Affiliations

  1. Facultad de Medicina, Posgrado en Ciencias Biologicas, Universidad Nacional Autonoma de Mexico (UNAM), Av. Ciudad Universitaria 3000, C.P. 04510, Coyoacan, Mexico City, Mexico

    Marcela Angelica De la Fuente-Hernandez & Vilma Maldonado Lagunas

  2. Epigenetics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periferico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P, 14610, Mexico City, Mexico

    Marcela Angelica De la Fuente-Hernandez, Erika Claudia Alanis-Manriquez, Karla Vazquez-Santillan & Vilma Maldonado Lagunas

  3. Gastrosurgery Service, UMAE. Hospital de Especialidades Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico

    Eduardo Ferat-Osorio & Arturo Rodriguez-Gonzalez

  4. Unidad de Investigacion Medica en Inmunoquimica. Hospital de Especialidades, Dr. Bernardo Sepulveda Gutierrez of the Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Av. Cuauhtemoc No 330, Col. Doctores, Cuauhtemoc, C.P., 06720, Mexico City, Mexico

    Lourdes Arriaga-Pizano

  5. Functional Cancer Genomics Laboratory, Instituto Nacional de Medicina Genomica (INMEGEN), Periférico Sur No. 4809, Col. Arenal Tepepan, Tlalpan, C.P., 14610, Mexico City, Mexico

    Jorge Melendez-Zajgla

  6. National Cancer Institute, San Fernando 22, Seccion XVI, Tlalpan, Mexico City, Mexico

    Veronica Fragoso-Ontiveros & Rosa Maria Alvarez-Gomez

Authors
  1. Marcela Angelica De la Fuente-Hernandez
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  2. Erika Claudia Alanis-Manriquez
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  3. Eduardo Ferat-Osorio
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  4. Arturo Rodriguez-Gonzalez
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  5. Lourdes Arriaga-Pizano
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  6. Karla Vazquez-Santillan
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  7. Jorge Melendez-Zajgla
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  8. Veronica Fragoso-Ontiveros
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  9. Rosa Maria Alvarez-Gomez
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  10. Vilma Maldonado Lagunas
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Contributions

MDH: substantial contributions to the conception and design of the study; substantial contributions to data acquisition and analysis and drafting the article. EAM: established the primary culture. EFO: contributed to the selection and enrollment of patients for obtaining visceral adipose tissue. ARG: contributed to the selection and enrollment of patients for obtaining visceral adipose tissue. LAP: contributed to the revision of the manuscript. KVS: contributed to the GSEA analysis of the RNAseq data. JMZ: made substantial contributions to the analysis and interpretation of sequencing data. VFO: contributed to the revision of the manuscript. RMAG: Contributed to the revision of the manuscript. VML: made substantial contributions to the conception and design of the study, coordinated the work, analyzed the data and contributed to the manuscript draft.

Corresponding author

Correspondence to Vilma Maldonado Lagunas.

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All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards and consent to participate.

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Not applicable. Inthe manuscript, no data is handled that puts the identity or privacy of the donor at risk.

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The authors declare that there is no conflict of interest.

Research involving human participants

Morbidly obese women undergoing gastric bypass donor visceral adipose tissue.

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Informed consent was obtained from all individual participants included in the study.

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De la Fuente-Hernandez, M.A., Alanis-Manriquez, E.C., Ferat-Osorio, E. et al. Molecular changes in adipocyte-derived stem cells during their interplay with cervical cancer cells. Cell Oncol. 45, 85–101 (2022). https://doi.org/10.1007/s13402-021-00653-6

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