ABSTRACT
In cancer, myeloid cells have tumor-supporting roles. We reported that the protein GPNMB (glycoprotein nonmetastatic B) was profoundly upregulated in macrophages interacting with tumor cells. Here, using mouse tumor models, we show that macrophage-derived soluble GPNMB increases tumor growth and metastasis in Gpnmb-mutant mice (DBA/2J). GPNMB triggers in the cancer cells the formation of self-renewing spheroids, which are characterized by the expression of cancer stem cell markers, prolonged cell survival and increased tumor-forming ability. Through the CD44 receptor, GPNMB mechanistically activates tumor cells to express the cytokine IL-33 and its receptor IL-1R1L. We also determined that recombinant IL-33 binding to IL-1R1L is sufficient to induce tumor spheroid formation with features of cancer stem cells. Overall, our results reveal a new paracrine axis, GPNMB and IL-33, which is activated during the cross talk of macrophages with tumor cells and eventually promotes cancer cell survival, the expansion of cancer stem cells and the acquisition of a metastatic phenotype.
Subject(s)
Fibrosarcoma/pathology , Hyaluronan Receptors/metabolism , Interleukin-33/metabolism , Lung Neoplasms/pathology , Macrophages/immunology , Membrane Glycoproteins/metabolism , Neoplastic Stem Cells/pathology , Animals , Apoptosis , Cell Proliferation , Fibrosarcoma/etiology , Fibrosarcoma/metabolism , Gene Expression Regulation, Neoplastic , Humans , Hyaluronan Receptors/genetics , Interleukin-33/genetics , Lung Neoplasms/etiology , Lung Neoplasms/metabolism , Male , Membrane Glycoproteins/genetics , Mice , Mice, Inbred DBA , Neoplastic Stem Cells/immunology , Neoplastic Stem Cells/metabolism , Sarcoma, Experimental/etiology , Sarcoma, Experimental/metabolism , Sarcoma, Experimental/pathology , Tumor Cells, Cultured , Xenograft Model Antitumor AssaysABSTRACT
Fractures of the humeral head are still challenging to decisions of indications, surgical skills and physiotherapy. 3- and 4-part-fractures of the humeral head in younger adults are still dominated by reconstructive osteosynthesis. New developments in osteosynthesis materials allow the surgeon to make use of minimal invasive techniques more often. Treatment of elderly patients with these injuries has changed within the last years. When it is obvious that the goal of a stable osteosynthesis can not be reached, shoulder prosthesis has become a primary treatment in elderly patients. New designs in shoulder prosthesis seem to lead to better functional results.