Stromal Lkb1 deficiency leads to gastrointestinal tumorigenesis involving the IL-11-JAK/STAT3 pathway.

Germline mutations in the gene encoding tumor suppressor kinase LKB1 lead to gastrointestinal tumorigenesis in Peutz-Jeghers syndrome (PJS) patients and mouse models; however, the cell types and signaling pathways underlying tumor formation are unknown. Here, we demonstrated that mesenchymal progenitor- or stromal fibroblast-specific deletion of Lkb1 results in fully penetrant polyposis in mice. Lineage tracing and immunohistochemical analyses revealed clonal expansion of Lkb1-deficient myofibroblast-like cell foci in the tumor stroma. Loss of Lkb1 in stromal cells was associated with induction of an inflammatory program including IL-11 production and activation of the JAK/STAT3 pathway in tumor epithelia concomitant with proliferation. Importantly, treatment of LKB1-defcient mice with the JAK1/2 inhibitor ruxolitinib dramatically decreased polyposis. These data indicate that IL-11-mediated induction of JAK/STAT3 is critical in gastrointestinal tumorigenesis following Lkb1 mutations and suggest that targeting this pathway has therapeutic potential in Peutz-Jeghers syndrome.

Gastrointestinal peptides and bone health.

PURPOSE OF REVIEW: To outline recent developments in research surrounding gastrointestinal peptides and their role in skeletal regulation. RECENT FINDINGS: Bone remodeling is influenced by many regulatory systems, which interact to ensure that the complex demands upon mineralized tissue are met without undue compromise. These include local actions such as mechanical factors, but are dominated by systemic endocrine factors. Although the involvement of hypothalamo-pituitary actions on bone homeostasis is well defined, growing evidence suggests that peripheral tissues and the circulating factors they produce represent an important regulatory axis in bone. Given the critical role of diet in mineral homeostasis, the gastrointestinal tract is a rich source of circulating factors capable of regulating bone homeostasis. After a review of manuscripts on known mechanisms and effects of gastrointestinal peptide on bone, these were summarized. SUMMARY: Although clearly an exciting and emergent field of research, more studies are required to define the specific actions of gastrointestinal regulator in bone, in particular, the relative contribution of systemic and local effects, to aid interpretation of their potential impact on human health and disease. Nonetheless, this exciting research will further our understanding on bone physiology and provide novel approaches to therapy in a wide range of skeletal conditions.