Establishing a xenograft mouse model of peritoneal dissemination of gastric cancer with organ invasion and fibrosis

Okazaki, Mitsuyoshi; Fushida, Sachio; Harada, Shinichi; Tsukada, Tomoya; Koyama, Jun; Oyama, Katsunobu; Miyashita, Tomoharu; Ninomiya, Itasu; Ohta, Tetsuo

doi:10.1186/s12885-016-2991-9

Cited by 13 publications

(10 citation statements)

References 38 publications

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“…As an immunogenic organ, allo‐ or xenografted skin by nature induces an immune response, ultimately leading to fibrotic encapsulation and rejection by the host . Murine xenograft models have been widely used for the investigation of fibrotic conditions; however, how the immune response to foreign grafts is linked to their clinically observed beneficial effects on wound healing has never been thoroughly investigated at the cellular or molecular levels.…”

Section: Discussionsupporting

confidence: 54%

Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model

Henn

Chen

Maan

et al. 2020

International Wound Journal

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Cryopreserved human skin allografts (CHSAs) are used for the coverage of major burns when donor sites for autografts are insufficiently available and have clinically shown beneficial effects on chronic non‐healing wounds. However, the biologic mechanisms behind the regenerative properties of CHSA remain elusive. Furthermore, the impact of cryopreservation on the immunogenicity of CHSA has not been thoroughly investigated and raised concerns with regard to their clinical application. To investigate the importance and fate of living cells, we compared cryopreserved CHSA with human acellular dermal matrix (ADM) grafts in which living cells had been removed by chemical processing. Both grafts were subcutaneously implanted into C57BL/6 mice and explanted after 1, 3, 7, and 28 days (n = 5 per group). A sham surgery where no graft was implanted served as a control. Transmission electron microscopy (TEM) and flow cytometry were used to characterise the ultrastructure and cells within CHSA before implantation. Immunofluorescent staining of tissue sections was used to determine the immune reaction against the implanted grafts, the rate of apoptotic cells, and vascularisation as well as collagen content of the overlaying murine dermis. Digital quantification of collagen fibre alignment on tissue sections was used to quantify the degree of fibrosis within the murine dermis. A substantial population of live human cells with intact organelles was identified in CHSA prior to implantation. Subcutaneous pockets with implanted xenografts or ADMs healed without clinically apparent rejection and with a similar cellular immune response. CHSA implantation largely preserved the cellularity of the overlying murine dermis, whereas ADM was associated with a significantly higher rate of cellular apoptosis, identified by cleaved caspase‐3 staining, and a stronger dendritic cell infiltration of the murine dermis. CHSA was found to induce a local angiogenic response, leading to significantly more vascularisation of the murine dermis compared with ADM and sham surgery on day 7. By day 28, aggregate collagen‐1 content within the murine dermis was greater following CHSA implantation compared with ADM. Collagen fibre alignment of the murine dermis, correlating with the degree of fibrosis, was significantly greater in the ADM group, whereas CHSA maintained the characteristic basket weave pattern of the native murine dermis. Our data indicate that CHSAs promote angiogenesis and collagen‐1 production without eliciting a significant fibrotic response in a xenograft model. These findings may provide insight into the beneficial effects clinically observed after treatment of chronic wounds and burns with CHSA.

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Section: Discussionsupporting

confidence: 54%

Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model

Henn

Chen

Maan

et al. 2020

International Wound Journal

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“…These mice are unable to generate an immune response against human cells and tumor engraftment is thus promoted in the peritoneal cavity. The xenografted PCa models have been studied using colon cancer (HCT-116, LS174T, HT29, SW480, SW620, LoVo, RKO, Caco-2, KM12, MDST8, HUTU80) [ 57 , 58 , 59 , 60 , 61 ], pancreatic cancer (Panc-1, TCC-Pan2, BxPC3, AsPC-1) [ 62 , 63 , 64 ], gastric cancer (60As6, HSC-44PE, HSC-58, MKN45-P) [ 56 , 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 , 66 , 67 , 68 , 69 ], and ovarian cancer (OVCAR3, OVCAR4, OVCAR5, OVCAR8, CAOV3, OVSAHO, OV2944-HM-1, SKOV-3) [ 59 , 70 , 71 , 72 ] cell lines. These models have been used to attain proofs of concept and explore treatments that determine in vivo tumor cell cytotoxicity of drugs, such as chemotherapeutic agents.…”

Section: Pca Mouse Modelsmentioning

confidence: 99%

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications

Bella

Trani

Fernandez‐Sendin

et al. 2021

Cancers

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Peritoneal carcinomatosis of primary tumors originating in gastrointestinal (e.g., colorectal cancer, gastric cancer) or gynecologic (e.g., ovarian cancer) malignancies is a widespread type of tumor dissemination in the peritoneal cavity for which few therapeutic options are available. Therefore, reliable preclinical models are crucial for research and development of efficacious treatments for this condition. To date, a number of animal models have attempted to reproduce as accurately as possible the complexity of the tumor microenvironment of human peritoneal carcinomatosis. These include: Syngeneic tumor cell lines, human xenografts, patient-derived xenografts, genetically induced tumors, and 3D scaffold biomimetics. Each experimental model has its own strengths and limitations, all of which can influence the subsequent translational results concerning anticancer and immunomodulatory drugs under exploration. This review highlights the current status of peritoneal carcinomatosis mouse models for preclinical development of anticancer drugs or immunotherapeutic agents.

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“…In recent years, intratumoral fibrosis has been focused on as a factor playing an important role in the infiltration of immunocompetent cells [11,24,26,27]. Although intratumoral fibrosis in peritoneal metastases has been reported to be very abundant [28,29], there have been few studies on local immunity in peritoneal metastases. Peritoneal metastases are well known to have treatment resistance and be associated with a poor prognosis, ostensibly because the infiltration of immunocompetent cells is suppressed by intratumoral fibrosis.…”

Section: Introductionmentioning

confidence: 99%

Abundant intratumoral fibrosis prevents lymphocyte infiltration into peritoneal metastases of colorectal cancer

et al. 2021

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Background Tumor-infiltrating lymphocytes (TILs) have been reported to reflect the anti-tumor immune status. However, recent investigations have demonstrated that intratumoral fibrosis is important as a factor affecting the infiltration of TILs. This study investigated the organ specificities of TIL infiltration and intratumoral fibrosis in primary colorectal cancer and distant metastases, as well as the relationship between the distribution of TILs and intratumoral fibrosis. Methods Patients who underwent resection of primary tumors or distant metastases for colorectal cancer with distant metastases were enrolled. We evaluated the TIL infiltration by immunohistochemical staining with CD3&CD8 and intratumoral fibrosis by immunohistochemical staining with α-SMA positive cancer-associated fibroblasts and Masson’s trichrome staining against collagen fibers. The "ImageJ" was used to evaluate fibrosis, and the density of TILs in the dense and sparse areas of fibrosis was calculated. The Immunoscore (IS) was obtained based on the density of CD3+/CD8+TILs in the tumor center and invasive margin of the primary tumor. Results The degree of CD3+/CD8+TIL infiltration in peritoneal metastases was significantly lower than that in liver and lung metastases. The area ratio of α-SMA positive cancer-associated fibroblasts and collagen fibers in peritoneal metastases was significantly higher than that of liver and lung metastases. Furthermore, the density of TILs in the high-fibrosis area was significantly lower than that in the low-fibrosis area. In the high-IS group of primary tumors, the degree of TIL infiltration in distant metastases was significantly higher than that in the low-IS group. Conclusion The infiltration of T lymphocytes into tumors is prevented in peritoneal metastases of colorectal cancer due to the high intratumoral fibrosis, which may lead to treatment resistance and a poor prognosis.

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Establishing a xenograft mouse model of peritoneal dissemination of gastric cancer with organ invasion and fibrosis

Cited by 13 publications

References 38 publications

Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model

Cryopreserved human skin allografts promote angiogenesis and dermal regeneration in a murine model

Mouse Models of Peritoneal Carcinomatosis to Develop Clinical Applications

Abundant intratumoral fibrosis prevents lymphocyte infiltration into peritoneal metastases of colorectal cancer

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