Microenvironmental regulation of cancer development

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Numerous studies have demonstrated that the tumor microenvironment not only responds to and supports carcinogenesis, but also actively contributes to tumor initiation, progression, and metastasis. During tumor progression all cells composing the tumor undergo phenotypic and epigenetic changes. Paracrine signaling between epithelial and stromal cells is important for the regulation of the proliferation, invasive, angiogenic, and metastatic behavior of cancer cells. Better understanding the molecular mechanisms by which stromal cells exert these effects may open up new venues for cancer therapeutic and preventative interventions.

Introduction

The ‘seed and soil’ hypothesis of tumor growth dates back as early as 1889 [1], but during the past decades advances in identifying aberrances in oncogenes and tumor suppressor genes within tumor epithelial cells resulted in the ignorance of the role of the microenvironment in tumorigenesis. However, a tumor is much more than clusters of transformed cells standing alone. Tumor epithelial cells can only thrive in an aberrant microenvironment composed of altered extracellular matrix (ECM) and various non-transformed cells (e.g. fibroblasts, myofibroblasts, leukocytes, and myoepithelial and endothelial cells) that play a role in the initiation and progression of neoplasms [2, 3, 4, 5]. Cross-talk between epithelial and stromal cells is known to be essential for differentiation and development of normal organs and tissues as well as for the growth and progression of tumors [2, 6, 7]. Recent work has begun to address the importance of the microenvironment in supporting malignant growth and the molecular mechanisms by which stromal cells may contribute to tumorigenesis. In this review, we focus on the phenotypic, genetic, and epigenetic alterations found in cells composing the tumor microenvironment, the role of these cells in tumor progression, and the clinical implications of these findings.

Section snippets

The tumor microenvironment: from reactive neighborhood to active contributor

It was noted long time ago that changes in the microenvironment accompany tumor formation [8, 9, 10]. Increased fibroblast proliferation and ECM remodeling are often found adjacent to cancer cells. The tumor stroma in many aspects resembles wound healing and chronic inflammatory conditions, except that normal physiologic controls are not maintained [11]. Furthermore, even fibroblasts outside of the immediate vicinity of neoplastic lesions can demonstrate phenotypic changes. For example, skin

Phenotypic and molecular alterations in the tumor microenvironment

To define the molecular basis underlying microenvironmental changes in tumorigenesis, Allinen et al. [36] characterized the comprehensive gene expression profiles of several major cell types from normal human breast tissue, ductal carcinoma in situ (DCIS), and invasive breast carcinomas, using serial analysis of gene expression (SAGE). The results of this study demonstrated that dramatic gene expression changes occur in all cell types, including tumor epithelial, endothelial, and myoepithelial

Signaling networks between the microenvironment and tumor epithelial cells

Stromal cells influence epithelial cell behavior by secreting various ECM proteins, chemokines, cytokines, growth factors, proteases, and protease inhibitors. A large proportion of genes differentially expressed in epithelial and stromal cells during breast tumor progression encode for secreted proteins and cell surface receptors [36]. An extensive network of cross-talks between cancer cells and the host was identified including regulations of cell-ECM interaction and growth factor signaling

The role of stromal cells in the in situ-to-invasive carcinoma progression

The transition of in situ to invasive carcinoma is a key event in breast tumor progression that is poorly understood. Phenotypic, genetic and epigenetic changes have been detected in tumor epithelial cells during this transition step yet stage-specific molecular signatures could not been identified [16, 17, 18, 19, 36, 46••]. Meanwhile, alterations in gene expression and DNA methylation occur in the non-transformed cells of the tumor microenvironment as well [36, 46••], implying that

Conclusions

Tumor initiation and progression are determined by the molecular and phenotypic alterations arising in the tumor epithelial cells as well as in their microenvironment. Thus, combined targeting of both the ‘seed’ and the ‘soil’ may be a more effective approach for cancer prevention and treatment.

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

Studies in this laboratory are supported by Novartis, NIH (CA89393, CA94074, and CA116235), DOD (W81XWH-07-1-029), ACS (RSG-05-154-01-MGO), and Avon Foundation grants to KP, and Susan G. Komen Foundation fellowship (PDF042234) to MH.

Disclosure: K.P. receives research support from and is a consultant to Novartis Pharmaceuticals, Inc. K.P. also receives research support from Biogen Idec, Inc. and is a consultant to and stock shareholder of Aveo Pharmaceuticals, Inc. K.P. and M.H. are also

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