Role in tumor biology

Treatment of malignancy by targeting of tumor-associated macrophages is an exciting and emerging concept. Direct correlations have been made between macrophage numbers, angiogenesis and tumor progression [6]. In some tumors the microenvironment appears to activate macrophage expression of soluble factors that: (i) promote angiogenesis, (ii) support tumor cell survival, proliferation, drug resistance, and motility, and (iii) suppress anti-tumor immunity (reviewed in Ref. [7]).

CSF-1 is overexpressed by many cancers, where it is a negative prognostic factor [8]. Preclinical studies have identified a role for CSF-1-dependent macrophages in tumor angiogenesis. Tumor angiogenesis is blunted in mice that are nullizygous for CSF-1, whereas forced overexpression of CSF-1, by either the host or the tumor, caused remarkable increases in tumor infiltrating macrophages and tumor vessel densities, as well as enhanced oncogenicity [9,10]. Pharmacological intervention studies corroborate a role for CSF-1 in tumor growth. CSF-1 antisense oligonucleotides, CSF-1 antibody, FMS siRNA, and a selective FMS kinase inhibitor have reduced the growth rates of diverse xenografts [11-13]. In these studies, tumor-associated macrophages and macro-phage-derived pro-angiogenic factors were depleted in association with marked reductions in tumor microvasculature. Anti-CSF-1 reversed the chemoresistance of MCF-7 xenografts, which identified an unanticipated role for CSF-1 in chemoresistance. Additionally, the siRNA, Mi160 was determined to inhibit CSF-1 synthesis and was, itself, down-regulated in several drug-resistant cancer lines [14]. Macrophages also mediate hormone resistance in prostate cancers by a nuclear receptor derepression pathway [15]. CSF-1-dependent macrophages also mediate tumor cell egress. In fact, spontaneous metastasis of mammary carcinomas of the lung is profoundly reduced in CSF-1-nullizygous mice [16,17].

High expression of FMS has been documented in several types of cancers [8]. The contribution of FMS to oncogenesis of these tumors remains speculative, but FMS inhibitors may, in some instances, have direct anticancer activity. Nonetheless, by targeting macrophages, FMS inhibitors may have broad utility in blocking critical tumor-stroma interactions.

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