Targeting stromal-cancer cell interactions with siRNAs.
ABSTRACT 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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- "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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ABSTRACT: The microenvironment of solid tumors is characterized by a reactive stroma with an abundance of inflammatory mediators and leukocytes, dysregulated vessels and proteolytic enzymes. TAM, major players in the connection between inflammation and cancer, summarize a number of functions (e.g., promotion of tumor cell proliferation and angiogenesis, incessant matrix turnover, repression of adaptive immunity), which ultimately have an important impact on disease progression. Thus, together with other myeloid-related cells present at the tumor site (Tie2 macrophages and MDSCs), TAM represent an attractive target of novel biological therapies of tumors.Journal of leukocyte biology 10/2009; 86(5):1065-73. DOI:10.1189/jlb.0609385 · 4.99 Impact Factor
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ABSTRACT: Median survival of patients with malignant glioma (MG) from time of diagnosis is approximately 1 year, despite surgery, irradiation and conventional chemotherapy. Improving patient outcome relies on our ability to develop more effective therapies that are directed against the unique molecular aberrations within a patient's tumor. Such molecularly targeted therapies may provide novel treatments that are more effective than conventional chemotherapeutics. Recently developed therapeutic strategies have focused on targeting several core glioma signaling pathways, including pathways mediated by growth-factors, PI3K/Akt/PTEN/mTOR, Ras/Raf/MEK/MAPK and other vital pathways. However, given the molecular diversity, heterogeneity and diverging and converging signaling pathways associated with MG, it is unlikely that any single agent will have efficacy in more than a subset of tumors. Overcoming these therapeutic barriers will require multiple agents that can simultaneously inhibit these processes, providing a rationale for combination therapies. This review summarizes the currently implemented single-agent and combination molecularly targeted therapies for MG.Expert Review of Neurotherapeutics 12/2009; 9(12):1815-36. DOI:10.1586/ern.09.116 · 2.83 Impact Factor