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Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity

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Ovarian Cancer: Molecular & Diagnostic Imaging and Treatment Strategies

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1330))

Abstract

The majority of ovarian cancer patients present clinically with wide-spread metastases throughout the peritoneal cavity, metastasizing to the mesothelium-lined peritoneum and visceral adipose depots within the abdomen. This unique metastatic tumor microenvironment is comprised of multiple cell types, including mesothelial cells, fibroblasts, adipocytes, macrophages, neutrophils, and T lymphocytes. Modeling advancements, including complex 3D systems and organoids, coupled with 2D cocultures, in vivo mouse models, and ex vivo human tissue cultures have greatly enhanced our understanding of the tumor-stroma interactions that are required for successful metastasis of ovarian cancer cells. However, advanced multifaceted model systems that incorporate frequency and spatial distribution of all cell types present in the tumor microenvironment of ovarian cancer are needed to enhance our knowledge of ovarian cancer biology in order to identify methods for preventing and treating metastatic disease. This review highlights the utility of recently developed modeling approaches, summarizes some of the resulting progress using these techniques, and suggests how these strategies may be implemented to elucidate signaling processes among cell types of the tumor microenvironment that promote ovarian cancer metastasis.

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References

  1. Lengyel, E. (2010). Ovarian cancer development and metastasis. American Journal of Pathology, 177(3), 1053–1064.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Mutsaers, S. E., Whitaker, D., & Papadimitriou, J. M. (2002). Stimulation of mesothelial cell proliferation by exudate macrophages enhances serosal wound healing in a murine model. The American Journal of Pathology, 160(2), 681–692.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Mutsaers, S. E. (2002). Mesothelial cells: Their structure, function and role in serosal repair. Respirology, 7, 171–191.

    Article  PubMed  Google Scholar 

  4. diZerega, G. S., & Campeau, J. D. (2001). Peritoneal repair and post-surgical adhesion formation. Human Reproduction Update, 7(6), 547–555.

    Article  CAS  PubMed  Google Scholar 

  5. Ye, Z. J., Yuan, M. L., Zhou, Q., Du, R. H., Yang, W. B., Xiong, X. Z., et al. (2012). Differentiation and recruitment of Th9 cells stimulated by pleural mesothelial cells in human Mycobacterium tuberculosis infection. PLoS One, 7(2), e31710.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Park, J. H., Kim, Y. G., Shaw, M., Kanneganti, T. D., Fujimoto, Y., Fukase, K., et al. (2007). Nod1/RICK and TLR signaling regulate chemokine and antimicrobial innate immune responses in mesothelial cells. Journal of Immunology, 179(1), 514–521.

    Article  CAS  Google Scholar 

  7. Chen, Y. T., Chang, Y. T., Pan, S. Y., Chou, Y. H., Chang, F. C., Yeh, P. Y., et al. (2014). Lineage tracing reveals distinctive fates for mesothelial cells and submesothelial fibroblasts during peritoneal injury. Journal of American Society of Nephrology, 25(12), 2847–2858.

    Article  CAS  Google Scholar 

  8. Mutsaers, S. E. (2004). The mesothelial cell. The International Journal of Biochemistry & Cell Biology, 36, 9–16.

    Article  CAS  Google Scholar 

  9. Kenny, H. A., Nieman, K. M., Mitra, A. K., & Lengyel, E. (2011). The first line of intra-abdominal metastatic attack: Breaching the mesothelial cell layer. Cancer Discovery, 1(2), 100–102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wilson, A. P. (1989). Mesothelial cells stimulate the anchorage-independent growth of human ovarian tumour cells. British Journal of Cancer, 59(6), 876–882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moser, T. L., Pizzo, S. V., Bafetti, L., Fishman, D. A., & Stack, M. S. (1996). Evidence for preferential adhesion of ovarian epithelial carcinoma cells to type I collagen mediated by the α2ß1 integrin. International Journal of Cancer, 67, 695–701.

    Article  CAS  PubMed  Google Scholar 

  12. Kenny, H. A., Chiang, C. Y., White, E. A., Schryver, E. M., Habis, M., Romero, I. L., et al. (2014). Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. Journal of Clinical Investigation, 124(10), 4614–4628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Offner, F. A., Obrist, P., Stadlmann, S., Feichtinger, H., Klingler, P., Herold, M., et al. (1995). IL-6 secretion by human peritoneal mesothelial and ovarian cancer cells. Cytokine, 7(6), 542–547.

    Article  CAS  PubMed  Google Scholar 

  14. Hart, P. C., Kenny, H. A., Grassl, N., Watters, K. M., Litchfield, L. M., Coscia, F., et al. (2019). Mesothelial cell HIF1alpha expression is metabolically downregulated by metformin to prevent oncogenic tumor-stromal crosstalk. Cell Reports, 29(12), 4086–98.e6.

    Article  CAS  PubMed  Google Scholar 

  15. Cannistra, S. A., Kansas, G. S., Niloff, J., DeFranzo, B., Kim, Y., & Ottensmeier, C. (1993). Binding of ovarian cancer cells to peritoneal mesothelium in vitro is partly mediated by CD44H. Cancer Research, 53(August 15), 3830–3838.

    CAS  PubMed  Google Scholar 

  16. Lee, J. G., Ahn, J. H., Jin Kim, T., Ho Lee, J., & Choi, J. H. (2015). Mutant p53 promotes ovarian cancer cell adhesion to mesothelial cells via integrin beta4 and Akt signals. Scientific Reports, 5, 12642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Lessan, K., Aguiar, D., Oegema, T. R., Siebenson, L., & Skubitz, A. P. (1999). CD44 and β1 integrin mediate ovarian carcinoma cell adhesion to peritoneal mesothelial cells. American Journal of Pathology, 154(5), 1525–1537.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Watanabe, T., Hashimoto, T., Sugino, T., Soeda, S., Nishiyama, H., Morimura, Y., et al. (2012). Production of IL1-beta by ovarian cancer cells induces mesothelial cell beta1-integrin expression facilitating peritoneal dissemination. Journal of Ovarian Research, 5(1), 7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Musrap, N., Karagiannis, G. S., Saraon, P., Batruch, I., Smith, C., & Diamandis, E. P. (2014). Proteomic analysis of cancer and mesothelial cells reveals an increase in Mucin 5AC during ovarian cancer and peritoneal interaction. Journal of Proteomics, 103, 204–215.

    Article  CAS  PubMed  Google Scholar 

  20. Sawada, K., Radjabi, A. R., Shinomiya, N., Kistner, E., Kenny, H., Becker, A. R., et al. (2007). c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Research, 67(4), 1670–1680.

    Article  CAS  PubMed  Google Scholar 

  21. Sandoval, P., Jiménez-Heffernan, J. A., Rynne-Vidal, A., Pérez-Lozano, M. L., Gilsanz, A., Ruiz-Carpio, V., et al. (2013). Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial to mesenchymal transition in peritoneal metastasis. Journal of Pathology, 231(4), 517–531.

    Article  CAS  PubMed  Google Scholar 

  22. Kenny, H. A., Krausz, T., Yamada, S. D., & Lengyel, E. (2007). Use of a novel 3D culture model to elucidate the role of mesothelial cells, fibroblasts and extra-cellular matrices on adhesion and invasion of ovarian cancer cells to the omentum. International Journal of Cancer, 121(7), 1463–1472.

    Article  CAS  PubMed  Google Scholar 

  23. Natarajan, S., Foreman, K. M., Soriano, M. I., Rossen, N. S., Shehade, H., Fregoso, D. R., et al. (2019). Collagen remodeling in the hypoxic tumor-mesothelial niche promotes ovarian cancer metastasis. Cancer Research, 79(9), 2271–2284.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Kenny, H. A., Lal-Nag, M., White, E. A., Shen, M., Chiang, C. Y., Mitra, A. K., et al. (2015). Quantitative high throughput screening using a primary human three-dimensional organotypic culture predicts in vivo efficacy. Nature Communications, 6, 6220.

    Article  CAS  PubMed  Google Scholar 

  25. Kenny, H. A., Lal-Nag, M., Shen, M., Kara, B., Nahotko, D. A., Wroblewski, K., et al. (2020). Quantitative high-throughput screening using an organotypic model identifies compounds that inhibit ovarian cancer metastasis. Molecular Cancer Therapeutics, 19(1), 52–62.

    Article  CAS  PubMed  Google Scholar 

  26. Rinkevich, Y., Mori, T., Sahoo, D., Xu, P. X., Bermingham, J. R., Jr., & Weissman, I. L. (2012). Identification and prospective isolation of a mesothelial precursor lineage giving rise to smooth muscle cells and fibroblasts for mammalian internal organs, and their vasculature. Nature Cell Biology, 14(12), 1251–1260.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Frantz, C., Stewart, K. M., & Weaver, V. M. (2010). The extracellular matrix at a glance. Journal of Cell Science, 123(Pt 24), 4195–4200.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. des Jardins-Park, H. E., Foster, D. S., & Longaker, M. T. (2018). Fibroblasts and wound healing: An update. Regenerative Medicine, 13(5), 491–495.

    Article  CAS  Google Scholar 

  29. Driskell, R. R., Lichtenberger, B. M., Hoste, E., Kretzschmar, K., Simons, B. D., Charalambous, M., et al. (2013). Distinct fibroblast lineages determine dermal architecture in skin development and repair. Nature, 504(7479), 277–281.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Otranto, M., Sarrazy, V., Bonte, F., Hinz, B., Gabbiani, G., & Desmouliere, A. (2012). The role of the myofibroblast in tumor stroma remodeling. Cell Adhesion & Migration, 6(3), 203–219.

    Article  Google Scholar 

  31. Ridky, T. W., Chow, J. M., Wong, D. J., & Khavari, P. A. (2010). Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia. Nature Medicine, 16(12), 1450–1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Attieh, Y., Clark, A. G., Grass, C., Richon, S., Pocard, M., Mariani, P., et al. (2017). Cancer-associated fibroblasts lead tumor invasion through integrin-beta3-dependent fibronectin assembly. The Journal of Cell Biology, 216(11), 3509–3520.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Sun, Y., Fan, X., Zhang, Q., Shi, X., Xu, G., & Zou, C. (2017). Cancer-associated fibroblasts secrete FGF-1 to promote ovarian proliferation, migration, and invasion through the activation of FGF-1/FGFR4 signaling. Tumour Biology, 39(7), 1010428317712592.

    PubMed  Google Scholar 

  34. Xu, L. N., Xu, B. N., Cai, J., Yang, J. B., & Lin, N. (2013). Tumor-associated fibroblast-conditioned medium promotes tumor cell proliferation and angiogenesis. Genetics and Molecular Research, 12(4), 5863–5871.

    Article  CAS  PubMed  Google Scholar 

  35. Cai, J., Tang, H., Xu, L., Wang, X., Yang, C., Ruan, S., et al. (2012). Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness. Carcinogenesis, 33(1), 20–29.

    Article  CAS  PubMed  Google Scholar 

  36. Yeung, T. L., Leung, C. S., Wong, K. K., Samimi, G., Thompson, M. S., Liu, J., et al. (2013). TGF-beta modulates ovarian cancer invasion by upregulating CAF-derived versican in the tumor microenvironment. Cancer Research, 73(16), 5016–5028.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Deying, W., Feng, G., Shumei, L., Hui, Z., Ming, L., & Hongqing, W. (2017). CAF-derived HGF promotes cell proliferation and drug resistance by up-regulating the c-Met/PI3K/Akt and GRP78 signalling in ovarian cancer cells. Bioscience Reports, 37(2), BSR20160470.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Kumar, D., New, J., Vishwakarma, V., Joshi, R., Enders, J., Lin, F., et al. (2018). Cancer-associated fibroblasts drive glycolysis in a targetable signaling loop implicated in head and neck squamous cell carcinoma progression. Cancer Research, 78(14), 3769–3782.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Curtis, M., Kenny, H. A., Ashcroft, B., Mukherjee, A., Johnson, A., Zhang, Y., et al. (2019). Fibroblasts mobilize tumor cell glycogen to promote proliferation and metastasis. Cell Metabolism, 29(1), 141–55.e9.

    Article  CAS  PubMed  Google Scholar 

  40. Gao, Q., Yang, Z., Xu, S., Li, X., Yang, X., Jin, P., et al. (2019). Heterotypic CAF-tumor spheroids promote early peritoneal metastasis of ovarian cancer. The Journal of Experimental Medicine, 216(3), 688–703.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oren, R., Addadi, Y., Narunsky Haziza, L., Dafni, H., Rotkopf, R., Meir, G., et al. (2016). Fibroblast recruitment as a tool for ovarian cancer detection and targeted therapy. International Journal of Cancer, 139(8), 1788–1798.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Li, W., Zhang, X., Wang, J., Li, M., Cao, C., Tan, J., et al. (2017). TGFbeta1 in fibroblasts-derived exosomes promotes epithelial-mesenchymal transition of ovarian cancer cells. Oncotarget, 8(56), 96035–96047.

    Article  PubMed  PubMed Central  Google Scholar 

  43. Romero, I. L., Mukherjee, A., Kenny, H. A., Litchfield, L. M., & Lengyel, E. (2015). Molecular pathways: Trafficking of metabolic resources in the tumor microenvironment. Clinical Cancer Research, 21(4), 680–686.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Yu, Y. H., & Ginsberg, H. N. (2005). Adipocyte signaling and lipid homeostasis: Sequelae of insulin-resistant adipose tissue. Circulation Research, 96(10), 1042–1052.

    Article  CAS  PubMed  Google Scholar 

  45. Lauby-Secretan, B., Scoccianti, C., Loomis, D., Grosse, Y., Bianchini, F., Straif, K., et al. (2016). Body fatness and cancer—Viewpoint of the IARC working group. The New England Journal of Medicine, 375(8), 794–798.

    Article  PubMed  PubMed Central  Google Scholar 

  46. Foong, K. W., & Bolton, H. (2017). Obesity and ovarian cancer risk: A systematic review. Post Reproductive Health, 23(4), 183–198.

    Article  PubMed  Google Scholar 

  47. Nieman, K. M., Kenny, H. A., Penicka, C. V., Ladanyi, A., Buell-Gutbrod, R., Zillhardt, M. R., et al. (2011). Adipocytes promote ovarian cancer metastasis and provide energy for rapid tumor growth. Nature Medicine, 17(11), 1498–1503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Guaita-Esteruelas, S., Guma, J., Masana, L., & Borras, J. (2018). The peritumoural adipose tissue microenvironment and cancer. The roles of fatty acid binding protein 4 and fatty acid binding protein 5. Molcular and Cellular Endocrinology, 462(Pt B), 107–118.

    Article  CAS  Google Scholar 

  49. Ladanyi, A., Mukherjee, A., Kenny, H. A., Johnson, A., Mitra, A. K., Sundaresan, S., et al. (2018). Adipocyte-induced CD36 expression drives ovarian cancer progression and metastasis. Oncogene, 37, 2285–2301.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Pascual, G., Avgustinova, A., Mejetta, S., Martin, M., Castellanos, A., Attolini, C. S., et al. (2017). Targeting metastasis-initiating cells through the fatty acid receptor CD36. Nature, 541(7635), 41–45.

    Article  CAS  PubMed  Google Scholar 

  51. John, B., Naczki, C., Patel, C., Ghoneum, A., Qasem, S., Salih, Z., et al. (2019). Regulation of the bi-directional cross-talk between ovarian cancer cells and adipocytes by SPARC. Oncogene, 38(22), 4366–4383.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Sun, C., Li, X., Guo, E., Li, N., Zhou, B., Lu, H., et al. (2020). MCP-1/CCR-2 axis in adipocytes and cancer cell respectively facilitates ovarian cancer peritoneal metastasis. Oncogene, 39(8), 1681–1695.

    Article  CAS  PubMed  Google Scholar 

  53. Jeffery, E., Berry, R., Church, C. D., Yu, S., Shook, B. A., Horsley, V., et al. (2014). Characterization of Cre recombinase models for the study of adipose tissue. Adipocytes, 3(3), 206–211.

    Article  CAS  Google Scholar 

  54. Wang, X., Deavers, M., Patenia, R., Bassett, R. L., Jr., Mueller, P., Ma, Q., et al. (2006). Monocyte/macrophage and T-cell infiltrates in peritoneum of patients with ovarian cancer or benign pelvic disease. Journal of Translational Medicine, 4, 30.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Liu, J., Geng, X., & Li, Y. (2016). Milky spots: Omental functional units and hotbeds for peritoneal cancer metastasis. Tumour Biology, 37(5), 5715–5726.

    Article  CAS  PubMed  Google Scholar 

  56. Zhang, M., He, Y., Sun, X., Li, Q., Wang, W., Zhao, A., et al. (2014). A high M1/M2 ratio of tumor-associated macrophages is associated with extended survival in ovarian cancer patients. Journal of Ovarian Research, 7, 19.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Kaneko, M., Nishida, M., & Iwasaki, H. (1985). A macrophage activating factor is present and active in the ascitic fluid of patients with ovarian cancer. Journal of Cancer Research and Clinical Oncology, 110(2), 131–135.

    Article  CAS  PubMed  Google Scholar 

  58. Liu, L., Wang, X., Li, X., Wu, X., Tang, M., & Wang, X. (2018). Upregulation of IGF1 by tumor-associated macrophages promotes the proliferation and migration of epithelial ovarian cancer cells. Oncology Reports, 39(2), 818–826.

    CAS  PubMed  Google Scholar 

  59. Carroll, M. J., Kapur, A., Felder, M., Patankar, M. S., & Kreeger, P. K. (2016). M2 macrophages induce ovarian cancer cell proliferation via a heparin binding epidermal growth factor/matrix metalloproteinase 9 intercellular feedback loop. Oncotarget, 7(52), 86608–86620.

    Article  PubMed  PubMed Central  Google Scholar 

  60. Ning, Y., Cui, Y., Li, X., Cao, X., Chen, A., Xu, C., et al. (2018). Co-culture of ovarian cancer stem-like cells with macrophages induced SKOV3 cells stemness via IL-8/STAT3 signaling. Biomedicine & Pharmacotherapy, 103, 262–271.

    Article  CAS  Google Scholar 

  61. Neyen, C., Pluddemann, A., Mukhopadhyay, S., Maniati, E., Bossard, M., Gordon, S., et al. (2013). Macrophage scavenger receptor a promotes tumor progression in murine models of ovarian and pancreatic cancer. Journal of Immunology, 190(7), 3798–3805.

    Article  CAS  Google Scholar 

  62. Hagemann, T., Wilson, J., Kulbe, H., Li, N. F., Leinster, D. A., Charles, K., et al. (2005). Macrophages induce invasiveness of epithelial cancer cells via NF-kappa B and JNK. Journal of Immunology, 175(2), 1197–1205.

    Article  CAS  Google Scholar 

  63. Yin, M., Li, X., Tan, S., Zhou, H. J., Ji, W., Bellone, S., et al. (2016). Tumor-associated macrophages drive spheroid formation during early transcoelomic metastasis of ovarian cancer. The Journal of Clinical Investigation, 126(11), 4157–4173.

    Article  PubMed  PubMed Central  Google Scholar 

  64. Carroll, M. J., Fogg, K. C., Patel, H. A., Krause, H. B., Mancha, A. S., Patankar, M. S., et al. (2018). Alternatively-activated macrophages upregulate mesothelial expression of P-selectin to enhance adhesion of ovarian cancer cells. Cancer Research, 78(13), 3560–3573.

    CAS  PubMed  PubMed Central  Google Scholar 

  65. Wang, X., Zhao, X., Wang, K., Wu, L., & Duan, T. (2013). Interaction of monocytes/macrophages with ovarian cancer cells promotes angiogenesis in vitro. Cancer Science, 104(4), 516–523.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Mantovani, A., Cassatella, M. A., Costantini, C., & Jaillon, S. (2011). Neutrophils in the activation and regulation of innate and adaptive immunity. Nature Reviews. Immunology, 11(8), 519–531.

    Article  CAS  PubMed  Google Scholar 

  67. Coffelt, S. B., Wellenstein, M. D., & de Visser, K. E. (2016). Neutrophils in cancer: Neutral no more. Nature Reviews. Cancer, 16(7), 431–446.

    Article  CAS  PubMed  Google Scholar 

  68. Shaul, M. E., & Fridlender, Z. G. (2019). Tumour-associated neutrophils in patients with cancer. Nature Reviews. Clinical Oncology, 16(10), 601–620.

    Article  PubMed  Google Scholar 

  69. Giuntoli, R. L., II, Webb, T. J., Zoso, A., Rogers, O., Diaz-Montes, T. P., Bristow, R. E., et al. (2009). Ovarian cancer-associated ascites demonstrates altered immune environment: Implications for antitumor immunity. Anticancer Research, 29(8), 2875–2884.

    CAS  PubMed  Google Scholar 

  70. Reinartz, S., Finkernagel, F., Adhikary, T., Rohnalter, V., Schumann, T., Schober, Y., et al. (2016). A transcriptome-based global map of signaling pathways in the ovarian cancer microenvironment associated with clinical outcome. Genome Biology, 17(1), 108.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Sokol, C. L., & Luster, A. D. (2015). The chemokine system in innate immunity. Cold Spring Harbor Perspectives in Biology, 7(5), a016303.

    Article  PubMed  PubMed Central  Google Scholar 

  72. Klink, M., Jastrzembska, K., Nowak, M., Bednarska, K., Szpakowski, M., Szyllo, K., et al. (2008). Ovarian cancer cells modulate human blood neutrophils response to activation in vitro. Scandinavian Journal of Immunology, 68(3), 328–336.

    Article  CAS  PubMed  Google Scholar 

  73. Charles, K. A., Kulbe, H., Soper, R., Escorcio-Correia, M., Lawrence, T., Schultheis, A., et al. (2009). The tumor-promoting actions of TNF-alpha involve TNFR1 and IL-17 in ovarian cancer in mice and humans. The Journal of Clinical Investigation, 119(10), 3011–3023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Lee, W., Ko, S. Y., Mohamed, M. S., Kenny, H. A., Lengyel, E., & Naora, H. (2018). Neutrophils facilitate ovarian cancer premetastatic niche formation in the omentum. Journal of Experimental Medicine, 216(1), 176–194.

    Article  CAS  PubMed  Google Scholar 

  75. Mayer, C., Darb-Esfahani, S., Meyer, A. S., Hubner, K., Rom, J., Sohn, C., et al. (2016). Neutrophil granulocytes in ovarian cancer—Induction of epithelial-to-mesenchymal-transition and tumor cell migration. Journal of Cancer, 7(5), 546–554.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Li, S., Cong, X., Gao, H., Lan, X., Li, Z., Wang, W., et al. (2019). Tumor-associated neutrophils induce EMT by IL-17a to promote migration and invasion in gastric cancer cells. Journal of Experimental & Clinical Cancer Research, 38(1), 6.

    Article  Google Scholar 

  77. Wang, Y., Chen, J., Yang, L., Li, J., Wu, W., Huang, M., et al. (2019). Tumor-contacted neutrophils promote metastasis by a CD90-TIMP-1 juxtacrine-paracrine loop. Clinical Cancer Research, 25(6), 1957–1969.

    Article  CAS  PubMed  Google Scholar 

  78. Al-Haidari, A. A., Algethami, N., Lepsenyi, M., Rahman, M., Syk, I., & Thorlacius, H. (2019). Neutrophil extracellular traps promote peritoneal metastasis of colon cancer cells. Oncotarget, 10(12), 1238–1249.

    Article  PubMed  PubMed Central  Google Scholar 

  79. Park, J., Wysocki, R. W., Amoozgar, Z., Maiorino, L., Fein, M. R., Jorns, J., et al. (2016). Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps. Science Translational Medicine, 8(361), 361ra138.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Jung, H. S., Gu, J., Kim, J. E., Nam, Y., Song, J. W., & Kim, H. K. (2019). Cancer cell-induced neutrophil extracellular traps promote both hypercoagulability and cancer progression. PLoS One, 14(4), e0216055.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Akk, A., Springer, L. E., Yang, L., Hamilton-Burdess, S., Lambris, J. D., Yan, H., et al. (2019). Complement activation on neutrophils initiates endothelial adhesion and extravasation. Molecular Immunology, 114, 629–642.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Witowski, J., Pawlaczyk, K., Breborowicz, A., Scheuren, A., Kuzlan-Pawlaczyk, M., Wisniewska, J., et al. (2000). IL-17 stimulates intraperitoneal neutrophil infiltration through the release of GRO alpha chemokine from mesothelial cells. Journal of Immunology, 165(10), 5814–5821.

    Article  CAS  Google Scholar 

  83. Rodrigues, I. S. S., Martins-Filho, A., Micheli, D. C., Lima, C. A., Tavares-Murta, B. M., Murta, E. F. C., et al. (2019). IL-6 and IL-8 as prognostic factors in peritoneal fluid of ovarian cancer. Immunological Investigations, 49, 510–521.

    Article  PubMed  CAS  Google Scholar 

  84. Yin, X., Wu, L., Yang, H., & Yang, H. (2019). Prognostic significance of neutrophil-lymphocyte ratio (NLR) in patients with ovarian cancer: A systematic review and meta-analysis. Medicine (Baltimore), 98(45), e17475.

    Article  Google Scholar 

  85. Barnes, T. A., & Amir, E. (2017). HYPE or HOPE: The prognostic value of infiltrating immune cells in cancer. British Journal of Cancer, 117(4), 451–460.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Shang, B., Liu, Y., Jiang, S. J., & Liu, Y. (2015). Prognostic value of tumor-infiltrating FoxP3+ regulatory T cells in cancers: A systematic review and meta-analysis. Scientific Reports, 5, 15179.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Zhang, G., Lu, J., Yang, M., Wang, Y., Liu, H., & Xu, C. (2020). Elevated GALNT10 expression identifies immunosuppressive microenvironment and dismal prognosis of patients with high grade serous ovarian cancer. Cancer Immunology, Immunotherapy, 69(2), 175–187.

    Article  CAS  PubMed  Google Scholar 

  88. Li, J., Wang, J., Chen, R., Bai, Y., & Lu, X. (2017). The prognostic value of tumor-infiltrating T lymphocytes in ovarian cancer. Oncotarget, 8(9), 15621–15631.

    Article  PubMed  PubMed Central  Google Scholar 

  89. Wefers, C., Duiveman-de Boer, T., Yigit, R., Zusterzeel, P. L. M., van Altena, A. M., Massuger, L., et al. (2018). Survival of ovarian cancer patients is independent of the presence of DC and T cell subsets in ascites. Frontiers in Immunology, 9, 3156.

    Article  CAS  PubMed  Google Scholar 

  90. Farhood, B., Najafi, M., & Mortezaee, K. (2019). CD8(+) cytotoxic T lymphocytes in cancer immunotherapy: A review. Journal of Cellular Physiology, 234(6), 8509–8521.

    Article  CAS  PubMed  Google Scholar 

  91. Togashi, Y., Shitara, K., & Nishikawa, H. (2019). Regulatory T cells in cancer immunosuppression—Implications for anticancer therapy. Nature Reviews. Clinical Oncology, 16(6), 356–371.

    Article  CAS  PubMed  Google Scholar 

  92. Wertel, I., Surowka, J., Polak, G., Barczynski, B., Bednarek, W., Jakubowicz-Gil, J., et al. (2015). Macrophage-derived chemokine CCL22 and regulatory T cells in ovarian cancer patients. Tumour Biology, 36(6), 4811–4817.

    Article  CAS  PubMed  Google Scholar 

  93. Bu, M., Shen, Y., Seeger, W. L., An, S., Qi, R., Sanderson, J. A., et al. (2016). Ovarian carcinoma-infiltrating regulatory T cells were more potent suppressors of CD8(+) T cell inflammation than their peripheral counterparts, a function dependent on TIM3 expression. Tumour Biology, 37(3), 3949–3956.

    Article  CAS  PubMed  Google Scholar 

  94. Idorn, M., Olsen, M., Halldorsdottir, H. R., Skadborg, S. K., Pedersen, M., Hogdall, C., et al. (2018). Improved migration of tumor ascites lymphocytes to ovarian cancer microenvironment by CXCR2 transduction. Oncoimmunology, 7(4), e1412029.

    Article  PubMed  Google Scholar 

  95. Goyne, H. E., Stone, P. J., Burnett, A. F., & Cannon, M. J. (2014). Ovarian tumor ascites CD14+ cells suppress dendritic cell-activated CD4+ T-cell responses through IL-10 secretion and indoleamine 2,3-dioxygenase. Journal of Immunotherapy, 37(3), 163–169.

    Article  CAS  PubMed  Google Scholar 

  96. Zhu, Q., Wu, X., Wu, Y., & Wang, X. (2016). Interaction between Treg cells and tumor-associated macrophages in the tumor microenvironment of epithelial ovarian cancer. Oncology Reports, 36(6), 3472–3478.

    Article  CAS  PubMed  Google Scholar 

  97. Zhao, H., Liao, X., & Kang, Y. (2017). Tregs: Where we are and what comes next? Frontiers in Immunology, 8, 1578.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Chen, X., Shang, W., Xu, R., Wu, M., Zhang, X., Huang, P., et al. (2019). Distribution and functions of gammadelta T cells infiltrated in the ovarian cancer microenvironment. Journal of Translational Medicine, 17(1), 144.

    Article  PubMed  PubMed Central  Google Scholar 

  99. Alvero, A. B., Montagna, M. K., Craveiro, V., Liu, L., & Mor, G. (2012). Distinct subpopulations of epithelial ovarian cancer cells can differentially induce macrophages and T regulatory cells toward a pro-tumor phenotype. American Journal of Reproductive Immunology, 67(3), 256–265.

    Article  CAS  PubMed  Google Scholar 

  100. Wu, M., Chen, X., Lou, J., Zhang, S., Zhang, X., Huang, L., et al. (2016). TGF-beta1 contributes to CD8+ Treg induction through p38 MAPK signaling in ovarian cancer microenvironment. Oncotarget, 7(28), 44534–44544.

    Article  PubMed  PubMed Central  Google Scholar 

  101. Kercher, E. M., Nath, S., Rizvi, I., & Spring, B. Q. (2020). Cancer cell-targeted and activatable photoimmunotherapy spares T cells in a 3D coculture model. Photochemistry and Photobiology, 96(2), 295–300.

    Article  CAS  PubMed  Google Scholar 

  102. Ando, Y., Siegler, E. L., Ta, H. P., Cinay, G. E., Zhou, H., Gorrell, K. A., et al. (2019). Evaluating CAR-T cell therapy in a hypoxic 3D tumor model. Advanced Healthcare Materials, 8(5), e1900001.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Kenny, H. A., Dogan, S., Zillhardt, M., Mitra, A. B., Yamada, S. D., Krausz, T., et al. (2009). Organotypic models of metastasis: A three dimensional culture mimicking the human peritoneum and omentum for the study of the early steps of ovarian cancer metastasis. Cancer Treatment and Research, 149, 335–351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Liebermann-Meffert, D. (2000). The greater omentum, anatomy, embryology, and surgical applications. The Surgical Clinics of North America, 80(1), 275–293.

    Article  CAS  PubMed  Google Scholar 

  105. Witz, C. A., Montoya-Rodriguez, I. A., Cho, S., Centonze, V. E., Bonewald, L., & Schenken, R. S. (2001). Composition of the extracellular matrix of the peritoneum. Journal of the Society for Gynecologic Investigation, 8(5), 299–304.

    Article  CAS  PubMed  Google Scholar 

  106. Peters, P. N., Schryver, E. M., Lengyel, E., & Kenny, H. (2015). Modeling the early steps of ovarian cancer dissemination in an organotypic culture of the human peritoneal cavity. Journal of Visualized Experiments, 106, e53541.

    Google Scholar 

  107. Kenny, H. A., & Lengyel, E. (2009). MMP-2 functions as an early response protein in ovarian cancer metastasis. Cell Cycle, 8(5), 683–688.

    Article  CAS  PubMed  Google Scholar 

  108. Kenny, H. A., Kaur, S., Coussens, L. M., & Lengyel, E. (2008). The initial steps of ovarian cancer cell metastasis are mediated by MMP-2 cleavage of vitronectin and fibronectin. The Journal of Clinical Investigation, 118(4), 1367–1379.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Kenny, H. A., Leonhardt, P., Ladanyi, A., Yamada, S. D., Montag, A., Im, H. K., et al. (2011). Targeting the urokinase plasminogen activator receptor inhibits ovarian cancer metastasis. Clinical Cancer Research, 17(3), 459–471.

    Article  CAS  PubMed  Google Scholar 

  110. Mitra, A. K., Chiang, C. Y., Tiwari, P., Tomar, S., Watters, K. M., Peter, M. E., et al. (2015). Microenvironment-induced downregulation of miR-193b drives ovarian cancer metastasis. Oncogene, 34(48), 5923–5932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Henry, C., Hacker, N., & Ford, C. (2017). Silencing ROR1 and ROR2 inhibits invasion and adhesion in an organotypic model of ovarian cancer metastasis. Oncotarget, 8(68), 112727–112738.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Sawada, K., Mitra, A. K., Radjabi, A. R., Bhaskar, V., Kistner, E., Tretiakova, M. S., et al. (2008). Loss of E-cadherin promotes ovarian cancer metastasis via alpha 5-integrin, which is a therapeutic target. Cancer Research, 68(7), 2329–2339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Kaur, S., Kenny, H. A., Jagadeeswaran, S., Zillhardt, M., Montag, A. G., Kistner, E., et al. (2009). β3-integrin expression on tumor cells inhibits tumor progression, reduces metastasis, and is associated with a favorable prognosis in patients with ovarian cancer. The American Journal of Pathology, 175(5), 2184–2196.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Lal-Nag, M., McGee, L., Guha, R., Lengyel, E., Kenny, H. A., & Ferrer, M. (2017). A high-throughput screening model of the tumor microenvironment for ovarian cancer cell growth. SLAS Discovery, 22(5), 494–506.

    CAS  PubMed  Google Scholar 

  115. Sehouli, J., Senyuva, F., Fotopoulou, C., Neumann, U., Denkert, C., Werner, L., et al. (2009). Intra-abdominal tumor dissemination pattern and surgical outcome in 214 patients with primary ovarian cancer. Journal of Surgical Oncology, 99(7), 424–427.

    Article  PubMed  Google Scholar 

  116. Wilkosz, S., Ireland, G., Khwaja, N., Walker, M., Butt, R., de Giorgio-Miller, A., et al. (2005). A comparative study of the structure of human and murine greater omentum. Anatomy and Embryology, 209(3), 251–261.

    Article  PubMed  Google Scholar 

  117. Krishnan, V., Clark, R., Chekmareva, M., Johnson, A., George, S., Shaw, P., et al. (2015). In vivo and ex vivo approaches to study ovarian cancer metastatic colonization of milky spot structures in peritoneal adipose. Journal of Visualized Experiments, 105, e52721.

    Google Scholar 

  118. Khan, S. M., Funk, H. M., Thiolloy, S., Lotan, T. L., Hickson, J., Prins, G. S., et al. (2010). In vitro metastatic colonization of human ovarian cancer cells to the omentum. Clinical & Experimental Metastasis, 27(3), 185–196.

    Article  Google Scholar 

  119. Clark, R., Krishnan, V., Schoof, M., Rodriguez, I., Theriault, B., Chekmareva, M., et al. (2013). Milky spots promote ovarian cancer metastatic colonization of peritoneal adipose in experimental models. The American Journal of Pathology, 183(2), 576–591.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Yung, M. M., Tang, H. W., Cai, P. C., Leung, T. H., Ngu, S. F., Chan, K. K., et al. (2018). GRO-alpha and IL-8 enhance ovarian cancer metastatic potential via the CXCR2-mediated TAK1/NFkappaB signaling cascade. Theranostics, 8(5), 1270–1285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. McGuire, S., Kara, B., Hart, P. C., Montag, A., Wroblewski, K., Fazal, S., et al. (2019). Inhibition of fascin in cancer and stromal cells blocks ovarian cancer metastasis. Gynecologic Oncology, 153(2), 405–415.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Berry, R., & Rodeheffer, M. S. (2013). Characterization of the adipocyte cellular lineage in vivo. Nature Cell Biology, 15(3), 302–308.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. Ieda, M., Fu, J. D., Delgado-Olguin, P., Vedantham, V., Hayashi, Y., Bruneau, B. G., et al. (2010). Direct reprogramming of fibroblasts into functional cardiomyocytes by defined factors. Cell, 142(3), 375–386.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Velletri, T., Villa, C. E., Lupia, M., Lo Riso, P., Luongo, R., Lopez Tobon, A., et al. (2018). Single cell derived organoids capture the self-renewing subpopulations of metastatic ovarian cancer. bioRXiv, 2018, 484121.

    Google Scholar 

  125. Fatehullah, A., Tan, S. H., & Barker, N. (2016). Organoids as an in vitro model of human development and disease. Nature Cell Biology, 18(3), 246–254.

    Article  PubMed  CAS  Google Scholar 

  126. Bartfeld, S., Bayram, T., van de Wetering, M., Huch, M., Begthel, H., Kujala, P., et al. (2015). In vitro expansion of human gastric epithelial stem cells and their responses to bacterial infection. Gastroenterology, 148(1), 126–36.e6.

    Article  PubMed  Google Scholar 

  127. Sato, T., Stange, D. E., Ferrante, M., Vries, R. G., Van Es, J. H., Van den Brink, S., et al. (2011). Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology, 141(5), 1762–1772.

    Article  CAS  PubMed  Google Scholar 

  128. Roerink, S. F., Sasaki, N., Lee-Six, H., Young, M. D., Alexandrov, L. B., Behjati, S., et al. (2018). Intra-tumour diversification in colorectal cancer at the single-cell level. Nature, 556(7702), 457–462.

    Article  CAS  PubMed  Google Scholar 

  129. Klotz, D. M., & Wimberger, P. (2017). Cells of origin of ovarian cancer: Ovarian surface epithelium or fallopian tube? Archives of Gynecology and Obstetrics, 296(6), 1055–1062.

    Article  PubMed  Google Scholar 

  130. Kurman, R. J. (2013). Origin and molecular pathogenesis of ovarian high-grade serous carcinoma. Annals of Oncology, 24(Suppl 10), x16–x21.

    Article  PubMed  Google Scholar 

  131. Auersperg, N. (2013). Ovarian surface epithelium as a source of ovarian cancers: Unwarranted speculation or evidence-based hypothesis? Gynecologic Oncology, 130(1), 246–251.

    Article  PubMed  Google Scholar 

  132. Auersperg, N. (2011). The origin of ovarian carcinomas: A unifying hypothesis. International Journal of Gynecological Pathology, 30(1), 12–21.

    Article  PubMed  Google Scholar 

  133. Flesken-Nikitin, A., Hwang, C. I., Cheng, C. Y., Michurina, T. V., Enikolopov, G., & Nikitin, A. Y. (2013). Ovarian surface epithelium at the junction area contains a cancer-prone stem cell niche. Nature, 495(7440), 241–245.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Zweemer, R. P., van Diest, P. J., Verheijen, R. H., Ryan, A., Gille, J. J., Sijmons, R. H., et al. (2000). Molecular evidence linking primary cancer of the fallopian tube to BRCA1 germline mutations. Gynecologic Oncology, 76(1), 45–50.

    Article  CAS  PubMed  Google Scholar 

  135. Rebbeck, T. R., Lynch, H. T., Neuhausen, S. L., Narod, S. A., Van’t Veer, L., Garber, J. E., et al. (2002). Prophylactic oophorectomy in carriers of BRCA1 or BRCA2 mutations. The New England Journal of Medicine, 346(21), 1616–1622.

    Article  PubMed  Google Scholar 

  136. Kessler, M., Hoffmann, K., Brinkmann, V., Thieck, O., Jackisch, S., Toelle, B., et al. (2015). The Notch and Wnt pathways regulate stemness and differentiation in human fallopian tube organoids. Nature Communications, 6, 8989.

    Article  CAS  PubMed  Google Scholar 

  137. Takahashi, K., Tanabe, K., Ohnuki, M., Narita, M., Ichisaka, T., Tomoda, K., et al. (2007). Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell, 131(5), 861–872.

    Article  CAS  PubMed  Google Scholar 

  138. Takahashi, K., & Yamanaka, S. (2006). Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell, 126(4), 663–676.

    Article  CAS  PubMed  Google Scholar 

  139. Yucer, N., Holzapfel, M., Jenkins Vogel, T., Lenaeus, L., Ornelas, L., Laury, A., et al. (2017). Directed differentiation of human induced pluripotent stem cells into fallopian tube epithelium. Scientific Reports, 7(1), 10741.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  140. Neel, B. G., Zhang, S., Zhang, T., Dolgalev, I., Ran, H., & Levine, D. A. (2018). Both fallopian tube and ovarian surface epithelium can act as cell-of-origin for high grade serous ovarian carcinoma. Nature Coomunications, 2018, 481200.

    Google Scholar 

  141. Watters, K. M., Bajwa, P., & Kenny, H. A. (2018). Organotypic 3D models of the ovarian cancer tumor microenvironment. Cancers (Basel), 10(8), 265.

    Article  CAS  Google Scholar 

  142. Hill, S. J., Decker, B., Roberts, E. A., Horowitz, N. S., Muto, M. G., Worley, M. J., Jr., et al. (2018). Prediction of DNA repair inhibitor response in short-term patient-derived ovarian cancer organoids. Cancer Discovery, 8(11), 1404–1421.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Kopper, O., de Witte, C. J., Lohmussaar, K., Valle-Inclan, J. E., Hami, N., Kester, L., et al. (2019). An organoid platform for ovarian cancer captures intra- and interpatient heterogeneity. Nature Medicine, 25, 838–849.

    Article  CAS  PubMed  Google Scholar 

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Hart, P.C., Bajwa, P., Kenny, H.A. (2021). Modeling the Early Steps of Ovarian Cancer Dissemination in an Organotypic Culture of the Human Peritoneal Cavity. In: Schatten, H. (eds) Ovarian Cancer: Molecular & Diagnostic Imaging and Treatment Strategies. Advances in Experimental Medicine and Biology, vol 1330. Springer, Cham. https://doi.org/10.1007/978-3-030-73359-9_5

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