Targeting Stromal-cancer Cell Interactions with siRNAs

Laboratory for Cardiovascular Research, Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria.
Methods in Molecular Biology (Impact Factor: 1.29). 02/2009; 487:243-66. DOI: 10.1007/978-1-60327-547-7_12
Source: PubMed


Tumors are composed of both malignant and normal cells, including fibroblasts, endothelial cells, mesenchymal stem cells, and inflammatory immune cells such as macrophages. These various stromal components interact with cancer cells to promote growth and metastasis. For example, macrophages, attracted by colony-stimulating factor-1 (CSF-1) produced by tumor cells, in turn produce various growth factors such as vascular endothelial growth factor, which supports the growth of tumor cells and their interaction with blood vessels leading to enhanced tumor cell spreading. The activation of autocrine and paracrine oncogenic signaling pathways by stroma-derived growth factors and cytokines has been implicated in promoting tumor cell proliferation and metastasis. Furthermore, matrix metalloproteinases (MMPs) derived from both tumor cells and the stromal compartment are regarded as major players assisting tumor cells during metastasis. Collectively, these recent findings indicate that targeting tumor-stroma interactions is a promising strategy in the search for novel treatment modalities in human cancer. This chapter summarizes our current understanding of the tumor microenvironment and highlights some potential targets for therapeutic intervention with small interfering RNAs.

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    • "Carcinogenesis is a multi-step process mediated by many growth factors including placental growth factor (PIGF), platelet-derived growth factor (PDGF), and Vascular Endothelial Growth Factor (VEGF) [60]. In the tumor microenvironment, the various growth factors control not only the cancer cells but also the stromal in autocrine and paracrine manner [61], [62]. VEGF is one of the key factors responsible for angiogenesis which controls the formation of new blood vessels from existing vasculature, and plays an essential role in tumor growth, invasion and metastasis [63], [64]. "
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    ABSTRACT: Liver cancer or hepatocellular carcinoma is one of the leading causes of cancer-related deaths. Conventional chemotherapies are limited by the development of drug resistance and various side effects. Because of its non-toxicity and potent biopharmacological activity, metabolites derived from mushrooms have received more attention in cancer therapy. Our previous studies have demonstrated the anticancer effects of polysaccharide-protein complexes derived from the Pleurotus mushrooms. The aim of this study was to investigate the underlying molecular mechanism of the anticancer activity of a hot water extract containing a polysaccharide-protein complex isolated from Pleurotus pulmonarius (PP) in liver cancer cells. Our results indicated that exposure of liver cancer cells to PP not only significantly reduced the in vitro cancer cell proliferation and invasion but also enhanced the drug-sensitivity to the chemotherapeutic drug Cisplatin. Both oral administration and intraperitoneal injection of PP significantly inhibited the tumor growth in xenograft BALB/c nude mice. PP triggered a marked suppression of the PI3K/AKT signaling pathway in liver cancer cells in vitro and in vivo, and overexpression of the constitutively active form of AKT, Myr-AKT, abrogated this effect and the inhibited proliferation and invasion by PP. Both western blot and ELISA results showed that PP-treated liver cancer cells had reduced expression and secretion of vascular endothelial growth factor (VEGF). Addition of recombinant human VEGF attenuated the inhibitory effects of PP on PI3K/AKT pathway and the cancer phenotypes. Our results demonstrated that PP suppressed the proliferation, invasion, and drug-resistance of liver cancer cells in vitro and in vivo, mediated by the inhibition of autocrine VEGF-induced PI3K/AKT signaling pathway. This study suggests the potential therapeutic implication of PP in the treatment of human liver cancer.
    Full-text · Article · Mar 2012 · PLoS ONE
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    • "As summarized above, TAM functional activities importantly contribute to the construction of the reactive tumor micro-environment and are, therefore, amenable targets of biological therapies. Macrophage depletion in experimental settings has been successful in decreasing tumor growth and metastatic spread [11,137,138]; furthermore their depletion may contribute to a better response to conventional chemotherapy and anti-angiogenic therapy [62,63,65-67]. Several approaches have been followed to target TAM in tumors such as inhibition of their recruitment at tumor sites or the use of cytotoxic drugs, for example, biphosponates. "
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    ABSTRACT: Tumor-Associated Macrophages (TAM) are key components of the reactive stroma of tumors. In most, although not all cancers, their presence is associated with poor patient prognosis. In addition to releasing cytokines and growth factors for tumor and endothelial cells, a distinguished feature of TAM is their high-rate degradation of the extra-cellular matrix. This incessant stroma remodelling favours the release of matrix-bound growth factors and promotes tumor cell motility and invasion. In addition, TAM produce matrix proteins, some of which are typical of the neoplastic tissues. The gene expression profile of TAM isolated from human tumors reveals a matrix-related signature with the up-regulation of genes coding for different matrix proteins, as well as several proteolytic enzymes. Among ECM components are: osteopontin, osteoactivin, collagens and fibronectin, including also a truncated isoform of fibronectin termed migration stimulation factor. In addition to serve as structural proteins, these matrix components have key functions in the regulation of the vessel network, in the inductionof tumor cell motility and degradation of cellular debris. Among proteolytic enzymes are: matrix metalloproteases, cathepsins, lysosomal and ADAM proteases, and the urokinase-type plasminogen activator. The degrading activity of TAM, coupled to the production of bio-active ECM proteins, co-operate to the build-up and maintenance of an inflammatory micro-environment which eventually promotes tumor progression.
    Full-text · Article · Dec 2011 · Cancers
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    • "Recent studies demonstrated that the tumor stroma does not exist simply as a passive support structure, but rather plays an active role in tumor progression (Blavier and Declerck, 2005; Derynck et al., 2001; Shekhar et al., 2001). In fact, the activation of autocrine and paracrine signaling pathways by stromaderived cytokines and growth factors has been implicated in promoting tumor cell proliferation and metastasis (Aharinejad et al., 2009). Therefore, elements of the tumor microenvironment are promising targets for novel therapies that may overcome many of the limitations of current treatment options that are primarily targeted to the cancer cell. "

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