Colony-Stimulating Factor-1 Blockade by Antisense Oligonucleotides and Small Interfering RNAs Suppresses Growth of Human Mammary Tumor Xenografts in Mice

Abstract

Colony-stimulating factor (CSF)-1 is the primary regulator of tissue macrophage production. CSF-1 expression is correlated with poor prognosis in breast cancer and is believed to enhance mammary tumor progression and metastasis through the recruitment and regulation of tumorassociated macrophages. Macrophages produce matrix metalloproteases (MMPs) and vascular endothelial growth factor, which are crucial for tumor invasion and angiogenesis. Given the important role of CSF-1, we hypothesized that blockade of CSF-1 or the CSF-1 receptor (the product of the c-fms proto-oncogene) would suppress macrophage infiltration and mammary tumor growth. Human MCF-7 mammary carcinoma cell xenografts in mice were treated with either mouse CSF-1 antisense oligonucleotide for 2 weeks or five intratumoral injections of either CSF-1 small interfering RNAs or c-fms small interfering RNAs. These treatments suppressed mammary tumor growth by 50%, 45%, and 40%, respectively, and selectively down-regulated target protein expression in tumor lysates. Host macrophage infiltration; host MMP-12, MMP-2, and vascular endothelial growth factor A expression; and endothelial cell proliferation within tumors of treated mice were decreased compared with tumors in control mice. In addition, mouse survival significantly increased after CSF-1 blockade. These studies demonstrate that CSF-1 and CSF-1 receptor are potential therapeutic targets for the treatment of mammary cancer.

Targeting tumor-associated macrophages in an orthotopic murine model of diffuse malignant mesothelioma

“…Transgenic mice that lack expression of CSF-1 and possess a predisposition to develop breast cancer show a delay in development of invasive and metastatic tumors when compared with WT mice (43). CSF-1 antisense RNA reduced growth of embryonic carcinoma and colon carcinoma xenografts accompanied by reduced expression of angiogenic factors and inhibition of tumor vascularity (44). Reduced tumor growth and vascularity was also reported following treatment of s.c. murine models of teratocarcinoma and rhabdomyosarcoma with CLIP (26).…”

Clodronate-liposome-mediated depletion of tumour-associated macrophages: a new and highly effective antiangiogenic therapy approach

“…Chemokines and chemokine receptors have been used as targets for the development of therapeutic strategies to control inflammatory disorders, and recent results suggest that chemokine inhibitors also affect tumour growth by reducing macrophage infiltration (Balkwill, 2004). Colony stimulating factor 1 (CSF-1), a cytokine commonly produced by tumours, triggers monocyte migration (Pixley and Stanley, 2004) and blocking CSF-1 or its receptor has been shown to suppress macrophage infiltration and to reduce tumour growth (Aharinejad et al, 2004). Recently, it was shown by Allavena et al (2005) that Yondelis (Trabectedin), a new anticancer agent of marine origin, markedly reduced the levels of proinflammatory cytokines CCL2 and IL-6 in monocytes and macrophages, thus inhibiting macrophage viability, differentiation and cytokine production.…”

Role of infiltrated leucocytes in tumour growth and spread

“…This was associated with a reduced serum concentration of CSF-1 and a decreased TAM density. Since mouse CSF-1 does not stimulate the human receptor, these data argue for the effects of the CSF-1 antisense molecules to be mediated through the reduction in TAMs (Aharinejad et al 2002).…”