Abstract
Cancer is associated with immune dysfunction characterized by the presence of proinflammatory and immunosuppressive cells and factors that contribute to tumor growth and progression. Here we show that mammary tumor growth is associated with defects in hematopoiesis, leading to myeloproliferative-like disease (leukemoid reaction), anemia, and disruption of the bone marrow stem/progenitor compartment. The defects we characterized included impaired erythropoiesis, leukocytosis, loss of early progenitor cells in the bone marrow, and splenic extramedullary hematopoiesis. We established an in vitro model to dissect interactions between mammary cancers and the hematopoietic system. Investigations in this model revealed that granulocyte colony-stimulating factor (G-CSF) produced by mammary tumors can synergize with FLT3L and granulocyte macrophage CSF (GM-CSF) to expand myeloid progenitors and their progeny in culture. Mammary tumor growth was associated with histone methylation changes within lineage-negative c-Kit-positive hematopoietic cells within the bone marrow of tumor-bearing mice. Similarly, parallel histone methylation patterns occurred in cultured bone marrow cells exposed to mammary tumor-conditioned cell culture media. Notably, changes in histone methylation in these cell populations correlated with dysregulated expression of genes controlling hematopoietic lineage commitment and differentiation, including Hox family genes and members of the Polycomb repressive complex 2 (PRC2) chromatin-remodeling complex. Together, our results show that mammary tumor-secreted factors induce profound perturbations in hematopoiesis and expression of key hematopoietic regulatory genes.
Highlights
The link between cancer and inflammation has been recognized for almost 150 years [1]
Cancer is frequently associated with immune system perturbations, with the tumor microenvironment known to reprogram myeloid cells into myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and/or tumorassociated dendritic cells (tDC)
Increased proportions and numbers of granulocytes and white blood cells (WBC) were observed in immunocompetent or immunocompromised (RAG1À/À) mammary tumor–bearing mice independent of injection site (MFP or s.c.; Supplementary Fig. S1 and Table 1, data not shown)
Summary
The link between cancer and inflammation has been recognized for almost 150 years [1]. Solid tumor development is often associated with cytokine and metabolite upregulation, and immunosuppressive cell expansion [including myeloid-derived suppressor cells (MDSC), T regulatory cells (Treg), tumor-associated macrophages (TAM), and tumorassociated dendritic cells (tDC)]. These cells facilitate tumor growth, metastasis, and immunological escape [2]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). A. Sio and M.K. Chehal contributed to this article
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