Mechanisms of Action of CSF-1 on Matrix Metalloproteases in Tumorigenesis

Matrix metalloproteinases (MMPs) foster cellular invasion by disrupting extracellular matrix (ECM) barriers and thereby facilitate tumor development. MMPs are synthesized not only by cancer cells but also by adjacent stromal cells, primarily macrophages. The production of macrophages is regulated by colony stimulating factor (CSF)-1. Our own results show that CSF-1 negative cancer cells upregulate host (mouse) CSF-1 production, and that inhibition of mouse CSF-1 by antisense oligonucleotides suppresses growth of human embryonic and colon cancer xenografts in mice. Associated with this suppression, there was a decrease in the expression of host CSF-1 and MMP-2. This proposal will focus on the molecular and cellular mechanisms involved in the interaction of CSF-1 and MMPs, leading to degradation of extracellular matrix in malignancies. We will use established in vitro and in vivo cancer models for identification of tumor derived factors that activate macrophages; the mechanisms underlying MMP expression in host stromal cells, primarily macrophages; and the role of MMPs in the progression of tumors. The proposed experiments are expected to expand our knowledge on basic biology of tumor-induced host CSF-1 and MMP upregulation and interaction, and can serve as a basis for furthering therapy in malignancies.

Colony-stimulating factor (CSF)-1 is the primary regulator of tissue macrophage production. CSF-1 over- expression is correlated with poor prognosis in a variety of tumors, and is believed to enhance tumor progression and metastasis through the recruitment and regulation of tumor-associated macrophages. Macrophages produce matrix metalloproteases (MMPs) and vascular endothelial growth factor, which are crucial for tumor invasion and angiogenesis and thereby facilitate tumor progression. Given the important role of CSF-1, this project characterized the mechanisms by which cancer cells upregulate tumor promoting factors in CSF-1-dependent macrophages, and investigated whether blockade of CSF-1 would suppress tumor growth. Our results show that a variety of cancer cells up-regulate host CSF-1 and MMP-2 expression via cancer cell-derived cytokines. Moreover, blockade of host CSF-1 significantly suppressed the growth of human colon and breast cancer in mice. In addition, the tumor vascularity and macrophage infiltration were reduced. Thus, CSF-1 blockade could be a novel strategy in treatment of solid tumors. The discovery of this essential function of CSF-1 in tumor growth received much attention and was quoted in several articles, which were published in top scientific journals.