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Because head and neck squamous cell carcinomas (HNSCC) are characterized by a distinct intertumorigenic and intratumorigenic heterogeneity, they often show substantial differences in the response to established therapy strategies. At present, a multitude of biologics and new pharmacological compounds for targeted therapies are available that allow more efficient and less toxic treatment. There is increasing pressure to establish predictive assays not only for ex ante analysis of the individual patient response to combined chemoradiotherapy and targeted therapies but also for investigation of the efficacy of new drugs. In this respect it is essential to maintain the pathophysiological tissue composition as it is known that paracrine tumor-stroma cell interactions may influence tumor reactivity to treatment. More complex models for individualized sensitivity testing have recently been described and the results are promising to pave the way for personalized cancer therapy. This review article focuses on different systems for maintaining the tumor microenvironment and hence the individual cellular composition, such as 3D organotypic models, organotypic multicellular spheroids, patient-derived xenografts and ex vivo tissue cultures and discusses the advantages and disadvantages in terms of translation into clinical application.

Disseminated tumor cells require a special microenvironment to form metastases. This metastatic niche is organ specific and forms prior to the establishment of visible metastases. The niche is characterized by vascular remodeling and bone marrow-derived cells which have migrated into it. Studies by other groups and our own results have already shown that intranodal lymphangiogenesis is an important prerequisite for regional lymph node metastases in rectal cancer patients, and can be used as a prognostic marker for progression-free survival. Niche cells such as endothelia secrete factors that attract tumor and bone marrow-derived cells. CXCL12 is one of these factors. CXCL12 activates the CXCR4 chemokine axis and induces migration along its gradient. Several factors, such as hypoxia, have been described to regulate CXCR4 function and surface expression on tumor cells. Low molecular weight agents have been used to block CXCR4 activation. This review focuses on the function and regulation of CXCR4 and its ligand CXCL12 in metastases formation. It also discusses potential options for therapeutic blockage.

With a 5-year survival rate that has remained stagnant at 6 % for decades, pancreatic ductal adenocarcinoma (PDAC) is still one of the most fatal malignancies. Despite intensive research, currently available therapy options are less than adequate. As more than half of the patients already show distant metastases at the time of diagnosis, metastatic disease should be a primary focus in the development of new therapeutic strategies. New findings from basic research provide various interesting approaches: molecular profiling of the primary tumor seems to be a possible method to gain knowledge about the prognosis, metastatic potential and therapy response of each individual case of PDAC. Certain subpopulations of cancer stem cells also seem to be of importance in metastasis of PDAC and could become potential therapeutic targets in the future. Interactions between tumor cells and their microenvironment are another crucial factor in the metastasis of pancreatic cancer and present various new starting points for potential therapies. As the number of cell types and signaling pathways that are found to play a role in PDAC metastasis continue to grow, the next big challenge will be to translate these findings into viable clinical applications.

The concept of a unidirectional cascade of metastatic events has been replaced in recent years by the metastatic cycle - the concept of a dynamic feed forward cycle of metastatic niches that evolve upon reciprocal interactions with the primary tumor and disseminating cancer cells. Primary tumors interact with pre-metastatic sites preparing organ-specific pre-metastatic niches. Metastasis-initiating cells home to and succumb to interactions with developing organ-specific metastatic niches, and secondary recirculating cancer cells interact back with the primary. Metastatic tropism as well as metastatic disease progression are a result of this feed forward cycle of dynamic, reciprocal interactions of cancer cells with their diverse metastatic niches. A better understanding of the multifaceted contributions of the organ-specific metastatic niches and their complex changes on cancer cell dissemination and of the mutual effects of the cellular and molecular mechanisms involved will open new avenues to better therapies for hitherto intractable progressive disease states of cancer patients and for adjuvant treatment options preventing relapses in tumor-free patients., (© 2014 Deutsche Dermatologische Gesellschaft (DDG). Published by John Wiley & Sons Ltd.)