Bone Marrow Homeostasis Is Impaired via JAK/STAT and Glucocorticoid Signaling in Cancer Cachexia Model

SIMPLE SUMMARY: Cancer cachexia is a systemic inflammatory disease characterized by the loss of muscle and fat and occurs in 50–80% of cancer patients. In cancer cachexia, the tumor tissues interact with other tissues and organs using secretory factors. Differentiated immune cells from hematopoietic stem cells (HSCs) of the bone marrow contribute to the systemic inflammation and may be affected by these intertissue interactions. However, the significant changes that occur in the bone marrow and the underlying mechanisms are still unclear. Here, we investigated the effects of cancer cachexia on bone and stem cells that reside in the bone marrow using a lung cancer cachexia animal model. Cancer cachexia induces bone loss and impairs the properties of the bone marrow mesenchymal stem cells via JAK/STAT and glucocorticoid signaling. Our findings provide new insights for developing a novel therapeutic strategy for cancer cachexia. ABSTRACT: Cancer cachexia is a multifactorial systemic inflammation disease caused by complex interactions between the tumor and host tissues via soluble factors. However, whether cancer cachexia affects the bone marrow, in particular the hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs), remains unclear. Here, we investigated the bone marrow and bone in a cancer cachexia animal model generated by transplanting Lewis lung carcinoma cells. The number of bone marrow mononuclear cells (BM-MNCs) started to significantly decrease in the cancer cachectic animal model prior to the discernable loss of muscle and fat. This decrease in BM-MNCs was associated with myeloid skewing in the circulation and the expansion of hematopoietic progenitors in the bone marrow. Bone loss occurred in the cancer cachexia animal model and accompanied the decrease in the bone marrow MSCs that play important roles in both supporting HSCs and maintaining bone homeostasis. Glucocorticoid signaling mediated the decrease in bone marrow MSCs in the cancer cachectic environment. The cancer cachexia environment also skewed the differentiation of the bone marrow MSCs toward adipogenic fate via JAK/STAT as well as glucocorticoid signaling. Our results suggest that the bone loss induced in cancer cachexia is associated with the depletion and the impaired differentiation capacity of the bone marrow MSCs.