Concepts of MetastasisIn 1889, the English surgeon Stephen Paget illustrated his theory on metastasis with the sentence 'When a plant goes to seed, its seeds are carried in all directions, but they can only live and grow if they fall on congenial soil'. He based this 'seed and soil' hypothesis on autopsy records where he detected a discrepancy between the blood supply and frequency of metastasis in specific organs. He concluded that the development of metastasis depends on distinctive features of the tumor cells as well as the specific target organs [1,2]. This concept replaced the mechanistic hypothesis of Rudolf Virchow who considered metastasis as the arrest of tumor cell emboli in the vasculature [2]. Nowadays, metastasis is understood as a complex process of molecular and biochemical events performed by multiple actors. The concept of a 'homogenous seed' has been replaced by a heterogeneous hierarchically organized system of tumorigenic cancer stem cells and their non-tumorigenic progeny [3]. Cancer stem cells are now regarded to be the major driver in metastasis development. In addition, the idea of a sequential development of a cancer from a single primary tumor to the subsequent spread to distant sites was abandoned in the last years and replaced by a model of a simultaneous progression towards metastatic tumor disease. The currently favored model describes the evolution of systemic tumor disease as a parallel development of primary tumor and distant metastasis caused by heterogeneous tumor subpopulations [4].To understand the cellular and molecular basis of metastasis, the most acknowledged approach is the concept of the invasionmetastasis cascade proposed by Isaiah J. Fidler in 2003 and subsequently adapted by Scott Valastyan in 2011 [5,6]. The authors distinguish 6 steps in the process from primary local tumor to distant Keywords Metastasis · Molecular mechanism · Cancer therapy Summary Background:The formation of distant metastases constitutes a complex process with a variety of different genes and pathways involved. To improve patient survival, it is necessary to understand the underlying mechanisms of metastasis to allow for targeted intervention. Methods: This review provides an overview of the general concepts of metastasis, focusing on the most important genes and pathways involved and on interventional strategies. Results: Cancer cells undergo different steps to form metastasis: most prominently, local invasion, intravasation, survival in the circulation, arrest at a distant organ site and extravasation, micrometastasis formation, and metastatic colonization. In order to pass these steps, different molecular pathways are of major importance: EGF/RAS/ RAF/MEK/ERK, PI3K/Akt/mTOR, HGF/Met, Wnt/ -catenin, and VEGF signaling. The HGF/Met regulator MACC1 and the Wnt signaling target S100A4 have been shown to play a major role in the metastatic process. Each gene and pathway provides an opportunity for therapeutic intervention. Conclusion: Since metastasis represents a highly limiting factor in cancer...

The CRS and HIPEC procedures have a proven survival benefit in selected patients. Due to the relatively high morbidity and mortality, the evaluation should be performed by an experienced team including a surgical oncologist, medical oncologist and intensive care physician, to achieve the highest rate of complete cytoreduction in combination with low morbidity; however, the effect of HIPEC has to be proven and the results of the randomized GASTRIPEC trial are awaited.

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Colorectal carcinoma (CRC) is associated with high incidence and mortality rate, particularly if metastasized to distant sites, such as the peritoneum. At time of first diagnosis 4 to 7 percent of the patients suffer from peritoneal metastasis (PM) of CRC. The PM is associated with poor prognosis and limited therapeutic options. Therefore, availability of adequate in vivo models for PM will promote the search for novel prognostic or even predictive biomarkers as well as the evaluation of chemosensitivity of PM towards standard, targeted and novel drugs. In this regard such models could be employed for more individualized concepts to improve the therapeutic outcome of PM patients. During the last decade patient-derived xenograft (PDX) mouse models have gained importance, since they closely resemble the molecular and biological features of the original primary tumors. However, until now no PM PDX models have been established from CRC. We therefore focused on the establishment and characterization of a novel CRC PM panel of PDX as useful platform for preclinical studies. For the PDX establishment colorectal surgical specimens were subcutaneously (s.c.) transplanted onto immunocompromized NOD scid gamma (NSG) mice. The successfully engrafted tumors were transferred to NMRI nu/nu mice for further passaging. Engrafted tumors were characterized by histopathology, immunohistochemistry and gene expression analyses using real-time RT-PCR. Chemosensitivity of PDX models was evaluated in vivo by application of a panel of conventional chemotherapeutic and of targeted drugs. For PDX establishment 68 CRC surgical specimens were transplanted onto NSG mice. From those, currently 22 PDX have engrafted and are stably growing on NMRI nu/nu mice. From those, 13 models of 10 patients have been analyzed. Their tumor doubling times ranged between 4 to 28 days. The histopathological evaluation revealed maintenance of the original CRC histology in the PDX. The chemosensitivity testing of conventional and of targeted drugs in the 13 PM PDX models revealed the individual, diverging response of the PDX, such as for 5-FU, irinotecan, oxaliplatin, cetuximab, and erlotinib. For selected PDX, orthotopic transplantation into the peritoneum revealed their potential to form disseminated tumors in kidney, ovaries and abdominal diaphragm. Our results demonstrate, that this novel panel of PDX maintains the morphology of the patient tumor in early passages, reflect heterogeneous response rates, and can be used as preclinical in vivo platform for translational studies of potential clinical use. In conclusion, this PDX panel of PM of the CRC can be used for further studies to evaluate new biomarker and to test novel therapies or combinations for PM of CRC. Citation Format: Wolfgang Walther, Eva Pachmayr, Bernadette Brzezicha, Britta Büttner, Beate Rau, Ulrike S. Stein. Patient-derived xenograft models from peritoneal metastasis of colorectal carcinoma as novel platform for biomarker analysis and drug testing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3853. doi:10.1158/1538-7445.AM2017-3853

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