Patient‐derived xenograft mouse models of pseudomyxoma peritonei recapitulate the human inflammatory tumor microenvironment

Abstract

Pseudomyxoma peritonei (PMP) is a neoplastic syndrome characterized by peritoneal tumor implants with copious mucinous ascites. The standard of care for PMP patients is aggressive cytoreductive surgery performed in conjunction with heated intraperitoneal chemotherapy. Not all patients are candidates for these procedures and a majority of the patients will have recurrent disease. In addition to secreted mucin, inflammation and fibrosis are central to PMP pathogenesis but the molecular processes that regulate tumor‐stromal interactions within the peritoneal tumor microenvironment remain largely unknown. This knowledge is critical not only to elucidate PMP pathobiology but also to identify novel targets for therapy. Here, we report the generation of patient‐derived xenograft (PDX) mouse models for PMP and assess the ability of these models to replicate the inflammatory peritoneal microenvironment of human PMP patients. PDX mouse models of low‐ and high‐grade PMP were generated and were of a similar histopathology as human PMP. Cytokines previously shown to be elevated in human PMP were also elevated in PDX ascites. Significant differences in IL‐6 and IL‐8/KC/MIP2 were seen between human and PDX ascites. Interestingly, these cytokines were mostly secreted by mouse‐derived, tumor‐associated stromal cells rather than by human‐derived PMP tumor cells. Our data suggest that the PMP PDX mouse models are especially suited to the study of tumor‐stromal interactions that regulate the peritoneal inflammatory environment in PMP as the tumor and stromal cells in these mouse models are of human and murine origins, respectively. These mouse models are therefore, likely to be useful in vivo surrogates for testing and developing novel therapeutic treatment interventions for PMP.

Enhanced computed tomography imaging features predict tumor grade in pseudomyxoma peritonei

“…Massive ascites in our study was more common in highgrade PMP, which is inconsistent with previous studies (15). Accumulation of ascites may be attributed to increased vascular permeability induced by cytokines, or blockage of lymphatic vessels (25). High-grade PMP could produce more ascites because (I) compared with low-grade PMP, high-grade PMP tumor cells release more cytokines, such as tumor necrosis factor-α (26), causing increased vascular permeability (27); and (II) enlarged abdominal lymph nodes, a reliable sign of lymph node involvement, can be only detected in high-grade PMP (15), and lymph node involvement is highly associated with lymphatic tumor thrombus formation (28,29), which results in the inability to remove excess fluid.…”

6-Gingerol stabilized the p-VEGFR2/VE-cadherin/β-catenin/actin complex promotes microvessel normalization and suppresses tumor progression

“…Samples with tumor sizes of 100–200 mm 3 were called F0. Subsequently, the samples were divided for passaging in vivo to obtain F1 and then F2 xenograft tumors as described above [26, 27]. When the F2 tumor size reached 100–200 mm 3 , the mice were randomly divided into six groups (eight mice each) and treated with saline, cisplatin, sorafenib, sorafenib/cisplatin, 6G or 6G/cisplatin to serve as the xenograft tumor model.…”

Zebrafish Xenograft: An Evolutionary Experiment in Tumour Biology

“…Transplantation studies in which human mammary cells are transplanted into mouse, however, show that there are some important differences in the microenvironment [ 80 ]. To get around this, some labs are working to “humanize” the transplant host using approaches ranging from expressing human cell markers in a given tissue to transplanting normal human tissue culture cells in the host along with the cancer cells [ 80 , 81 ]. We need to ask how much of their behaviour is conserved when cells are put into an evolutionary divergent context, such as the zebrafish xenograft.…”