Abstract
Ovarian cancer is the most common cause of death from gynecological cancer. Understanding the biology of this disease, particularly how tumor-associated lymphocytes and fibroblasts contribute to the progression and metastasis of the tumor, has been impeded by the lack of a suitable tumor xenograft model. We report a simple and reproducible system in which the tumor and tumor stroma are successfully engrafted into NOD-scid IL2Rγnull (NSG) mice. This is achieved by injecting tumor cell aggregates derived from fresh ovarian tumor biopsy tissues (including tumor cells, and tumor-associated lymphocytes and fibroblasts) i.p. into NSG mice. Tumor progression in these mice closely parallels many of the events that are observed in ovarian cancer patients. Tumors establish in the omentum, ovaries, liver, spleen, uterus, and pancreas. Tumor growth is initially very slow and progressive within the peritoneal cavity with an ultimate development of tumor ascites, spontaneous metastasis to the lung, increasing serum and ascites levels of CA125, and the retention of tumor-associated human fibroblasts and lymphocytes that remain functional and responsive to cytokines for prolonged periods. With this model one will be able to determine how fibroblasts and lymphocytes within the tumor microenvironment may contribute to tumor growth and metastasis, and will make it possible to evaluate the efficacy of therapies that are designed to target these cells in the tumor stroma.
Highlights
Both normal and neoplastic human tissues have been successfully engrafted into T cell and B cell-deficient prkdcscid mice
It was established previously that the subcutaneous implantation of solid pieces of fresh human tumor tissues into NSG mice resulted in the establishment of tumor microenvironments [5]. The advantages of this approach over previous methods were that the resultant xenografts maintained their original architecture, including tumor-associated leukocytes, stromal fibroblast and tumor cells, and the xenografts survived for prolonged periods without HVG interference or infiltration of host cells
A major limitation of this earlier xenograft model was that it failed to reflect the patterns of tumor growth and spreading that are observed in cancer patients, and some tumors failed to engraft or resulted in xenografts with large areas of necrosis due to an inadequate vascularization of the solid pieces of tumors
Summary
Both normal and neoplastic human tissues have been successfully engrafted into T cell and B cell-deficient prkdcscid (scid) mice. While scid mice lacked functional B and T cells, these mice had an intact innate immune response that was responsible for the complex cellular and molecular HVG response. The intensity of this HVG response varied considerably from mouse to mouse and with the histological type of tumor used for engraftment [3]. A major breakthrough was the generation of immunodeficient mice that are homozygous for targeted mutations at the interleukin-2 receptor c chain locus [2] These mice are severely impaired in the development and function of T cells, B cells and NK cells [2]. Immunodeficient mice lacking the IL-2 receptor c chain have been found to support the prolonged engraftment of human hematopoietic cells and peripheral blood mononuclear cells [2] better than previous immunodeficient mouse strains
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