Context-specific roles for paracrine IL-6 in lymphomagenesis

A basic requirement for the development of complex organ systems is that the cellular response to identical environmental cues can vary significantly between distinct cell types and developmental stages. While it is well established that paracrine signaling can similarly elicit diverse responses in distinct tumor types, the relevance of developmental stage-specific signaling responses to tumor development remains unclear. Here, we show that the same microenvironmental factor, IL-6, can both promote and prevent lymphoma development by acting on cells at distinct stages of hematopoietic development. Specifically, paracrine IL-6 signaling promotes the survival of transplanted hematopoietic stem cells following lethal irradiation, allowing for the persistence and expansion of progenitor cells bearing a cancer-promoting alteration. Conversely, IL-6 signaling also initiates a paracrine secretory program in the bone marrow that promotes B-cell differentiation and inhibits the development of B-cell malignancies. Thus, stage-specific responses to cytokines may promote progenitor cell expansion while also inhibiting neoplastic development within a single developmental lineage. Once transformed, the resulting B-cell lymphomas again use paracrine IL-6 signaling as a survival signal, highlighting the ability of tumor cells to co-opt pathways used for stem cell protection. These data not only suggest a complex regulation of tumor development by the preneoplastic microenvironment, but also that this regulation can decisively impact the outcome of wellestablished tumor modeling approaches.