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

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.

Translatability and transferability of in silico models: Context of use switching to predict the effects of environmental chemicals on the immune system

“…Central immune system's functions are referred to as functions. The UISS is particularly concerned with the diversity of specific elements, restriction of major histocompatibility classes [61] , clonal selection by antigen affinity [62] , thymus education of T cells [63] , antigen processing and presentation (both the cytosolic and endocytic pathways are used) [64] , cell–cell cooperation [65] , homeostasis of bone marrow-derived cells [66] , hypermutation of antibodies [67] , cellular and humoral responses [68] , and immune memory [69] . Time is discrete in UISS, as it is in most ABM techniques [70] .…”

Targeting cancer cachexia: Molecular mechanisms and clinical study

“…Bone loss occurs in cancer cachexia animal models, accompanied by decrease in bone marrow mesenchymal stem cells, and the number of bone marrow mononuclear cells begins to decrease significantly before significant loss of muscles and fat. 218 Myelogenous suppressor cells (MDSCs) are induced by proinflammatory cytokines and represent immature myeloid cell populations at different stages. They exist not only in the bone marrow but also in secondary lymphoid organs, such as the spleen and lymph nodes.…”

“…Immune cells differentiated from bone marrow hematopoietic stem cells play an important role in systemic inflammation and may be related to the interaction between organs during cancer cachexia. Bone loss occurs in cancer cachexia animal models, accompanied by decrease in bone marrow mesenchymal stem cells, and the number of bone marrow mononuclear cells begins to decrease significantly before significant loss of muscles and fat 218 . Myelogenous suppressor cells (MDSCs) are induced by proinflammatory cytokines and represent immature myeloid cell populations at different stages.…”

Pathological features of tissues and cell populations during cancer cachexia

“…Moreover, mesenchymal stromal cells in bone marrow that are multipotent and can differentiate into different cell types (ex. adipocytes, osteoblasts; (Pittenger et al, 1999)), lose their colony-forming ability and differentiation potential after LLC-induced cancer cachexia due to activation of JAK/STAT and glucocorticoid signaling (Yu et al, 2021).…”