Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype

<p>Abstract</p> <p>Background</p> <p>Pseudomyxoma peritonei (PMP) is a rare malignant disease, most commonly originating from appendiceal lesions and characterized by accumulation of mucinous tumor tissue in the peritoneal cavity. Since the disease is infrequent, the task of carrying out studies of treatment efficacy and disease biology in the clinical setting is challenging, warranting the development of relevant <it>in vitro </it>and <it>in vivo </it>PMP models.</p> <p>Methods</p> <p>Human tumor tissue was implanted in the peritoneal cavity of nude mice to establish two orthotopic models exhibiting noninvasive intraperitoneal growth without metastasis development.</p> <p>Results</p> <p>Xenograft tissues have retained essential properties of the original human tumors, such as macro- and microscopic growth patterns, mucin production as well as expression of carcinoembryonal antigen, cytokeratins 20 and 7 and the proliferation marker pKi67. Upon microscopic examination, the human tumors were categorized as the PMCA-I (peritoneal mucinous carcinomatosis of intermediate features) subtype, which was conserved through 14 examined passages in mice, for the first time modeling this particular histopathologic category.</p> <p>Conclusion</p> <p>In conclusion, two novel orthotopic models of human PMP have been established that consistently portray a distinct histopathologic subtype and reflect essential human tumor properties. Xenografts can easily and reproducibly be transferred to new generations of mice with acceptable passage periods, rendering the models as attractive tools for further studies of PMP biology and treatment.</p

Roadmap for a precision-medicine initiative in the Nordic region

The Nordic region, comprising primarily Denmark, Estonia, Finland, Iceland, Norway and Sweden, has many of the necessary characteristics for being at the forefront of genome-based precision medicine. These include egalitarian and universal healthcare, expertly curated patient and population registries, biobanks, large population-based prospective cohorts linked to registries and biobanks, and a widely embraced sense of social responsibility that motivates public engagement in biomedical research. However, genome-based precision medicine can be achieved only through coordinated action involving all actors in the healthcare sector. Now is an opportune time to organize scientists in the Nordic region, together with other stakeholders including patient representatives, governments, pharmaceutical companies, academic institutions and funding agencies, to initiate a Nordic Precision Medicine Initiative. We present a roadmap for how this organization can be created. The Initiative should facilitate research, clinical trials and knowledge transfer to meet regional and global health challenges.Non peer reviewe

Anti-Angiogenic Treatment in Pseudomyxoma Peritonei - Still a Strong Preclinical Rationale

Pseudomyxoma peritonei (PMP) is a rare, slow-growing cancer characterized by progressive accumulation of intraperitoneal mucinous tumor deposits. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) cures approximately 50% of patients, but in unresectable and recurrent cases, treatment options are limited. Anti-angiogenic treatment is being explored as a potential therapeutic option. Using PMP patient samples, microvessel densities (immunostaining for CD31 and CD105) and pro-angiogenic factors were analyzed, and the proliferative response upon incubation with human umbilical cord vascular endothelial cells (HUVEC) was determined. Growth inhibition by anti-angiogenic drugs was analyzed in patient-derived xenograft models of PMP. PMP tumor tissues were found to be highly vascularized and contained key pro-angiogenic factors, in particular related to vascular endothelial growth factor (VEGF) signaling, but interestingly, high levels of fibroblast growth factor 2 were also detected. HUVEC proliferation was stimulated upon incubation with fresh tumor samples and the observed proliferation could be inhibited by VEGF pathway inhibitor bevacizumab. In xenograft models the two VEGF pathway inhibitors, bevacizumab and aflibercept, inhibited tumor growth. This work reemphasizes the importance of angiogenesis as a major driver in PMP and strengthens the preclinical rationale for continued exploration of angiogenesis inhibition in the hope of providing novel treatment to a group of patients that have few other treatment options

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype-0

<p><b>Copyright information:</b></p><p>Taken from "Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype"</p><p>http://www.biomedcentral.com/1471-2407/7/116</p><p>BMC Cancer 2007;7():116-116.</p><p>Published online 30 Jun 2007</p><p>PMCID:PMC1920528.</p><p></p>inated the picture with tumor lesions identified on the surface of the urinary bladder, liver hilum and mesentery of the small intestine. B) Passage 0 of the PMP-2 model exhibited almost exclusively large, "solid" tumors adherent to intraperitoneal surfaces such as liver hilum, retroperitoneum and urinary bladder

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype-2

<p><b>Copyright information:</b></p><p>Taken from "Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype"</p><p>http://www.biomedcentral.com/1471-2407/7/116</p><p>BMC Cancer 2007;7():116-116.</p><p>Published online 30 Jun 2007</p><p>PMCID:PMC1920528.</p><p></p>as observed in primary tumors, main surgical specimens and in all specimens harvested from the first six animal passages, here illustrated by sections from PMP-1 passage 1. CK7, on the other hand was hardly expressed in the PMP-1 series (panel C), whereas the PMP-2 model (passage 2) exhibited high expression of this cytokeratin (panel D), showing a distinct phenotypic difference between otherwise very similar tumors. Intra- and extracellular mucin was present in all examined sections (panel E). A high fraction of pKi67 positive cells was detected, and in this PMP-1 passage 3 tumor 10–50% of tumor cell nuclei were stained (panel F)

Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype-1

<p><b>Copyright information:</b></p><p>Taken from "Pseudomyxoma peritonei – two novel orthotopic mouse models portray the PMCA-I histopathologic subtype"</p><p>http://www.biomedcentral.com/1471-2407/7/116</p><p>BMC Cancer 2007;7():116-116.</p><p>Published online 30 Jun 2007</p><p>PMCID:PMC1920528.</p><p></p> models, respectively. In both patients, primary tumor manifestations were appendiceal lesions; (A) Patient 1: cystadenoma of the appendix with low grade atypia. (E) Patient 2: mucinous adenocarcinoma, the selected section illustrating an area of invasive growth in the appendiceal wall. Peritoneal lesions from the main surgical specimens were remarkably similar in the two patients, exhibiting focal areas of cribriform growth and nuclear stratification (B and F), but in both cases, the histopathologic picture was dominated by strips of bland epithelium lining large accumulations of extracellular mucin (C and G). In xenografts from both models a similar histological growth pattern was observed, with adenomucinosis as the dominating manifestation, but with focal areas of nuclear stratification and cribriform growth, leading to classification as PMCA-I (D and H)