BackgroundRho GTPases play important roles in cytoskeleton organization, cell cycle progression and are key regulators of tumor progression. Strategies to modulate increased Rho GTPase activities during cancer progression could have therapeutic potential.MethodsWe report here the characterization of a Cdc42-selective small-molecule inhibitor AZA197 for the treatment of colon cancer that was developed based on structural information known from previously developed compounds affecting Rho GTPase activation. We investigated the effects of AZA197 treatment on RhoA, Rac1 and Cdc42 activities and associated molecular mechanisms in colon cancer cells in vitro. Therapeutic effects of AZA197 were examined in vivo using a xenograft mouse model of SW620 human colon cancer cells. After treatment, tumors were excised and processed for Ki-67 staining, TUNEL assays and Western blotting to evaluate proliferative and apoptotic effects induced by AZA197.ResultsIn SW620 and HT-29 human colon cancer cells, AZA197 demonstrated selectivity for Cdc42 without inhibition of Rac1 or RhoA GTPases from the same family. AZA197 suppressed colon cancer cell proliferation, cell migration and invasion and increased apoptosis associated with down-regulation of the PAK1 and ERK signaling pathways in vitro. Furthermore, systemic AZA197 treatment reduced tumor growth in vivo and significantly increased mouse survival in SW620 tumor xenografts. Ki-67 staining and tissue TUNEL assays showed that both inhibition of cell proliferation and induction of apoptosis associated with reduced PAK/ERK activation contributed to the AZA197-induced therapeutic effects in vivo.ConclusionsThese data indicate the therapeutic potential of the small-molecule inhibitor AZA197 based on targeting Cdc42 GTPase activity to modulate colorectal cancer growth.
Crosstalk between stromal cells and malignant cells within the tumor microenvironment is important for tumorigenesis. According to current clinical and experimental evidence, tumor associated macrophages (TAMs) play a major role in tumor progression to metastasis in different cancers. In breast cancer, increased number of TAMs is associated with poor prognosis. Previous work in our laboratory has shown that depletion of TAMs by blocking colony-stimulating factor-1 (CSF-1) suppresses tumor growth, matrix metalloprotease production and further recruitment of macrophages in a MCF-7 breast cancer xenograft model. In this study, we aim to investigate Interleukin-34 (IL-34), a novel ligand for the colony stimulating factor-1 receptor (CSF-1R). IL-34 functions as a specific and independent ligand and as an agonist to the CSF-1R. Furthermore it is known to induce proliferation through mitogen activated protein kinase (MAPK) activation in macrophages and cancer cells. To date, nothing is known about the role of IL-34 in breast cancer and its effects on downstream signalling pathway modulation in cancer cell-macrophage crosstalk. Our real-time PCR data shows that in co-cultures with murine macrophages, human MCF-7 and MDA-MB-231 breast cancer cells express increased levels of IL-34. In addition, in vitro migration assays demonstrated that recombinant human and murine IL-34 significantly increases the migration of murine macrophages, MCF-7 and MDA-MB-231 breast cancer cells. IL-34 also increased the proliferation of murine macrophages and breast cancer cells. Experiments on the protein level demonstrated the activation of MAPK/ERK in murine macrophages and breast cancer cells by recombinant IL-34. These preliminary data indicate that TAM-breast cancer cell interactions induce IL-34 production associated with induction of proliferation and the migratory capacity of tumor and stromal cells, which together may influence the invasiveness of the developing tumor. Here we propose IL-34 as a target for the treatment of breast cancer which may affect the accumulation of TAMs and improve breast cancer prognosis. Citation Format: Sandun Gunawardhana, Karin Zins, Trevor Lucas, Dietmar Abraham. Novel CSF-1 receptor ligand IL-34 modulates macrophage-breast cancer cell crosstalk. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1160. doi:10.1158/1538-7445.AM2014-1160
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