The Fibroblastic Coconspirator in Cancer Progression

Department of Anatomy, University of California, San Francisco, 94143-0452, USA.
Cold Spring Harbor Symposia on Quantitative Biology 02/2005; 70(1):383-8. DOI: 10.1101/sqb.2005.70.007
Source: PubMed


A remarkable change has occurred in the thinking about epithelial-derived cancer in recent years: From almost entirely focusing on oncogenes and tumor suppressor genes has come the realization that the tumor microenvironment is a coconspirator in the carcinogenic process. Many types of stromal cells, including fibroblasts, adipocytes, macrophages, mast cells, and cells of the vascular system, are crucial contributors to epithelial carcinogenesis. Here, we focus on the fibroblast's role in cancer progression and the molecules involved in the communications between the fibroblasts and the cancer cells, including fibroblast secreted protein 1 (FSP-1 or S100A4), transforming growth factor beta (TGF-beta), the chemokine CXCL-12 (stromal derived factor 1 alpha, SDF-1alpha), type I collagen, and matrix metalloproteinase 13 (MMP-13).

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Available from: Laurie E Littlepage, Mar 14, 2014
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    • "Recent evidence suggests that the HIF1α locus is selectively lost in ccRCC tumors during progression to higher stages [18]. Carcinoma is increasingly being characterized as a metabolic disease based on the cancer cells’ dependence on various necessary nutrients from healthy surrounding cells [19], [20], or the dysregulation of metabolic machinery to ensure continued growth [21]. In particular, ccRCC tumors display unique metabolic features that define the cancer in genomic investigations [22], [23]. "
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    ABSTRACT: Background Hypoxia Inducible Factors (HIF1α and HIF2α) are commonly stabilized and play key roles related to cell growth and metabolic programming in clear cell renal cell carcinoma. The relationship of these factors to discretely alter cell metabolic activities has largely been described in cancer cells, or in hypoxic conditions, where other confounding factors undoubtedly compete. These transcription factors and their specific roles in promoting cancer metabolic phenotypes from the earliest stages are poorly understood in pre-malignant cells. Methods We undertook an analysis of SV40-transformed primary kidney epithelial cells derived from newborn mice genetically engineered to express a stabilized HIF1α or HIF2α transgene. We examined the metabolic profile in relation to each gene. Results Although the cells proliferated similarly, the metabolic profile of each genotype of cell was markedly different and correlated with altered gene expression of factors influencing components of metabolic signaling. HIF1α promoted high levels of glycolysis as well as increased oxidative phosphorylation in complete media, but oxidative phosphorylation was suppressed when supplied with single carbon source media. HIF2α, in contrast, supported oxidative phosphorylation in complete media or single glucose carbon source, but these cells were not responsive to glutamine nutrient sources. This finding correlates to HIF2α-specific induction of Glul, effectively reducing glutamine utilization by limiting the glutamate pool, and knockdown of Glul allows these cells to perform oxidative phosphorylation in glutamine media. Conclusion HIF1α and HIF2α support highly divergent patterns of kidney epithelial cell metabolic phenotype. Expression of these factors ultimately alters the nutrient resource utilization and energy generation strategy in the setting of complete or limiting nutrients.
    PLoS ONE 05/2014; 9(5):e98705. DOI:10.1371/journal.pone.0098705 · 3.23 Impact Factor
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    • "Tumor angiogenesis is an important factor in proliferation, metastasis, and drug sensitivity. Primary tumors without vasculature are small and dormant, while the growth of the tumor mass creates hypoxic conditions in the center of the tumor that induce expression of VEGF and subsequent tumor vascularization [75]. CAFs are also suggested to be an important source for growth factors and cytokines recruiting endothelial cells. "
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    ABSTRACT: Tumors are not merely masses of neoplastic cells but complex tissues composed of cellular and noncellular elements. This review provides recent data on the main components of a dynamic system, such as carcinoma associated fibroblasts that change the extracellular matrix (ECM) topology, induce stemness and promote metastasis-initiating cells. Altered production and characteristics of collagen, hyaluronan and other ECM proteins induce increased matrix stiffness. Stiffness along with tumor growth-induced solid stress and increased interstitial fluid pressure contribute to tumor progression and therapy resistance. Second, the role of immune cells, cytokines and chemokines is outlined. We discuss other noncellular characteristics of the tumor microenvironment such as hypoxia and extracellular pH in relation to neoangiogenesis. Overall, full understanding of the events driving the interactions between tumor cells and their environment is of crucial importance in overcoming treatment resistance and improving patient outcome.
    Cancer Cell International 05/2014; 14(1):41. DOI:10.1186/1475-2867-14-41 · 2.77 Impact Factor
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    • "The TME is composed of several cell types depending on the stage of tumor development. During the initial stages of tumor development and in the case of tumors in situ, TME is largely composed of ductal epithelial and myoepithelial cells, while in the later stages of tumor progression, namely, during invasive disease, TME is composed of several cell-types such as fibroblasts, endothelial cells, mammary epithelial cells, adipocytes and immune cells [5],[7],[9]. Several recent studies have indicated that cancer associated fibroblasts and immune cells present in the TME communicate with breast cancer cells to facilitate tumorigenesis [6], [10]–[13]. "
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    ABSTRACT: Exosomes are nanovesicles originating from multivesicular bodies and are released by all cell types. They contain proteins, lipids, microRNAs, mRNAs and DNA fragments, which act as mediators of intercellular communications by inducing phenotypic changes in recipient cells. Tumor-derived exosomes have been shown to play critical roles in different stages of tumor development and metastasis of almost all types of cancer. One of the ways by which exosomes affect tumorigenesis is to manipulate the tumor microenvironments to create tumor permissive "niches". Whether breast cancer cell secreted exosomes manipulate epithelial cells of the mammary duct to facilitate tumor development is not known. To address whether and how breast cancer cell secreted exosomes manipulate ductal epithelial cells we studied the interactions between exosomes isolated from conditioned media of 3 different breast cancer cell lines (MDA-MB-231, T47DA18 and MCF7), representing three different types of breast carcinomas, and normal human primary mammary epithelial cells (HMECs). Our studies show that exosomes released by breast cancer cell lines are taken up by HMECs, resulting in the induction of reactive oxygen species (ROS) and autophagy. Inhibition of ROS by N-acetyl-L-cysteine (NAC) led to abrogation of autophagy. HMEC-exosome interactions also induced the phosphorylation of ATM, H2AX and Chk1 indicating the induction of DNA damage repair (DDR) responses. Under these conditions, phosphorylation of p53 at serine 15 was also observed. Both DDR responses and phosphorylation of p53 induced by HMEC-exosome interactions were also inhibited by NAC. Furthermore, exosome induced autophagic HMECs were found to release breast cancer cell growth promoting factors. Taken together, our results suggest novel mechanisms by which breast cancer cell secreted exosomes manipulate HMECs to create a tumor permissive microenvironment.
    PLoS ONE 05/2014; 9(5):e97580. DOI:10.1371/journal.pone.0097580 · 3.23 Impact Factor
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