Exploring the peritoneal surface malignancy phenotype—a pilot immunohistochemical study of human pseudomyxoma peritonei and derived animal models

Flatmark, Kjersti; Davidson, Ben; Kristian, Alexandr; Stavnes, Helene Tuft; Førsund, Mette; Reed, Wenche

doi:10.1016/j.humpath.2009.12.013

Cited by 29 publications

(22 citation statements)

References 39 publications

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“…The PMP PDX tumors expressed proteins that have been shown to be enriched in (but not restricted to) human PMP tumors such as caudal type homeobox 2 (CDX2), cytokeratin 20 (CK20), E‐Cadherin, MUC2, and Mucin 5AC (MUC5AC) (Fig. H–Z’) . CDX2, a homeodomain transcription factor, has been shown to be critical for MUC2 expression in intestinal goblet cells .…”

Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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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.

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Section: Resultsmentioning

confidence: 99%

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

et al. 2016

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“…The clinical samples used for establishment of the animal models from human tumor tissues were previously described. 12,13 In the present work, mucinous tumor tissue harvested at the time of surgery from two additional patients with clinical PMP was used in short-term cultures to study ex vivo immunotoxin efficacy and cell-death mechanisms. The study was approved by the regional ethics board of south-east Norway and written informed consent was obtained from the patients.…”

Section: Clinical Samplesmentioning

confidence: 99%

“…The establishment and propagation of the five human orthotopic models of PMP and mucinous peritoneal carcinomatosis were previously described. 12,13 Briefly, the tumor models were established by implanting human mucinous tumor tissue from patients undergoing cytoreductive surgery of the peritoneal cavity. The macroscopic growth pattern of the models closely resembled their human counterparts, with strict i.p.…”

Section: Animal Experimentsmentioning

confidence: 99%

“…It would be tempting to speculate that the observed differential sensitivity might reflect the aggressiveness of the tumor models, because the PMCA-2 and PMCA-3 models were derived from patients with aggressive histology, whereas the PMP-2 model represents an intermediate histological subtype, originating from an appendiceal cystadenoma. 12 However, and perhaps more likely, molecular characteristics independent of histological subtype might determine the sensitive phenotype, but presently no specific determinant of MMC sensitivity has been defined. For MOC31PE, the best indicative factor is cell surface antigen expression, which was essentially similar in all the models as assessed by immunohistochemistry.…”

Section: Cancer Therapymentioning

confidence: 99%

“…11 We previously reported the establishment, propagation and validation of five orthotopic animal models of human mucinous peritoneal surface malignancies. 12,13 In our work, the utility of the models for studying experimental treatment was demonstrated by comparing the efficacy of two drugs commonly used for i.p. cancer treatment in humans, mitomycin C (MMC) and oxaliplatin (OXA).…”

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confidence: 99%

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Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies

Flatmark¹,

Guldvik

Svensson

et al. 2013

Int. J. Cancer

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Cytoreductive surgery and intraperitoneal (i.p.) chemotherapy constitute a curative treatment option in mucinous peritoneal surface malignancies of intestinal origin, but treatment outcome is highly variable and the search for novel therapies is warranted. Immunotoxins are attractive candidates for targeted therapy in the peritoneal cavity because of direct cytotoxicity, distinct mechanisms of action and tumor cell selectivity. The MOC31PE immunotoxin targets the tumor-associated adhesion protein EpCAM (Epithelial Cell Adhesion Molecule), and has been administered safely in early clinical trials. In our work, the efficacy of i.p. administration of MOC31PE alone and together with mitomycin C (MMC) was investigated in unique animal models of human mucinous peritoneal surface malignancies. In initial model validation experiments, clear differences in efficacy were demonstrated between MMC and oxaliplatin, favoring MMC in five investigated tumor models. Subsequently, MOC31PE and MMC were given as single i.p. injections alone and in combination. In the PMCA-2 model, moderate growth inhibition was obtained with both drugs, while the combination resulted in at least additive effects; whereas the PMP-2 model was highly sensitive to both drugs separately and in combination and intermediate sensitivity was found for the PMCA-3 model. Furthermore, results from ex vivo experiments on freshly obtained mucinous tumor tissue from animals and patients suggested that classic mechanisms of immunotoxin activity were involved, i.e., inhibition of protein synthesis and induction of apoptosis. The present results suggest that adding MOC31PE to MMC-based i.p. chemotherapy should be further explored for EpCAM-expressing peritoneal surface malignancies, and a phase I trial is in preparation.Mucinous peritoneal surface malignancies of intestinal origin encompass a range of clinical presentations, from the clinically benign manifestation pseudomyxoma peritonei (PMP) to aggressive mucinous peritoneal carcinomatosis from colorectal cancer. Histopathological presentation varies, with increasing cellular atypia, high epithelium to mucin ratio and signet ring cell differentiation being associated with an aggressive phenotype. The treatment is, regardless of histology, aimed at complete surgical removal of all visible tumor deposits followed by chemotherapy, typically some type of perioperative intraperitoneal (i.p.) chemotherapy, often supplemented with postoperative systemic chemotherapy. Prognosis is highly dependent on histopathological subtype, and particularly in peritoneal mucinous carcinomatosis (PMCA), the search for more efficacious chemotherapy regimens is warranted. [1][2][3] Although the benefit of cytoreductive surgery is well documented in mucinous peritoneal surface malignancies, the optimal chemotherapeutic strategy has not been proven. [2][3][4] Several drug combinations and delivery strategies are currently being pursued, mostly in early clinical trials, while preclinical assessment of drug efficacy has been impeded by lack o...

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CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

Gao

et al. 2019

Journal Cellular Physiology

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Tight junction is a structural constitution in cell-cell adhesion and play an important role in the maintenance of permeability and integrity of normal epithelial cell barrier.The protein encoded by Claudin 1 (CLDN1), a member of the claudin family, is an integral membrane protein and a component of tight junction strands. CLDN1 has been proved to regulate the proliferation and metastasis of multiple tumors, but little is known about its role in esophageal squamous cell carcinoma (ESCC). Here, we found that CLDN1 was aberrantly increased in ESCC tissues and cell lines, and mainly distributed in the nucleus of tumor cells. Furthermore, we confirmed that CLDN1 promoted the proliferation and metastasis of ESCC by triggering autophagy both in vitro and in vivo. Mechanically, we validated that CLDN1-induced autophagy via increasing Unc-51 like autophagy activating kinase 1 (ULK1) expression through AMP-activated protein kinase (AMPK)/signal transducer and activator of transcription 1 (STAT1) signaling pathway in ESCC cells. Taken together, our findings demonstrated that aberrant expression and distribution of CLDN1 promoted the proliferation and metastasis of esophageal squamous carcinoma by triggering autophagy through AMPK/STAT1/ULK1 signaling pathway. K E Y W O R D S AMPK/STAT1/ULK1 signaling, autophagy, CLDN1, esophageal squamous cell carcinoma, proliferation, and metastasis

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Exploring the peritoneal surface malignancy phenotype—a pilot immunohistochemical study of human pseudomyxoma peritonei and derived animal models

Cited by 29 publications

References 39 publications

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

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

Immunotoxin targeting EpCAM effectively inhibits peritoneal tumor growth in experimental models of mucinous peritoneal surface malignancies

CLDN1 induces autophagy to promote proliferation and metastasis of esophageal squamous carcinoma through AMPK/STAT1/ULK1 signaling

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