Re-assessing the role of concomitant tumor resistance
Moritz Felcht

Studies in men and mice suggest that a primary tumor can actively inhibit the formation of secondary malignancies. This has been termed concomitant tumor resistance (CTR). For example, clinical studies revealed that in certain tumor entities – e.g. breast cancer - the majority of metastases develop metachrone after excision of the primary tumor. More specific, most of these macrometastases grow within a certain time window of three to four years after primary tumor removal. These clinical data are supported by pre-clinical studies, which prove that the presence of a primary tumor can actively inhibit the formation of secondary malignancies in different murine metastases models. CTR takes these clinical and pre-clinical observations into account and suggests that a primary tumor secrets immunogenic and non-immunogenic factors, esp. angiogenic factors, that inhibit the late steps of the metastatic cascade. Indeed, a handful of factors have been identified which support the concept of CTR. Yet, up to now, none of these factors was translated successfully into cancer therapy. In an unbiased screen of more than 5000 tumor patients’ samples, we identified an angiogenic factor with pro- and anti-angiogenic functions. We could show that this factor can locally act and enhance tumor growth and at the same time, when systemically released, inhibit macrometastases formation. These mutual opposing effects can be explained by specific control of expression of the factor and variants thereof as well as contextual signaling. Currently, we are using this knowledge for developing new therapeutic strategies to inhibit metastases formation.