Tumor–stroma interactions

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The importance of stromal cells and the factors that they express during cancer initiation and progression has been highlighted by recent literature. The cellular components of the stroma of epithelial tissues are well-recognized as having a supportive role in carcinogenesis, where the initiating mutations of a tumor originate in the epithelial cells. The use of mouse models and xenografts suggests that mutations in the stromal fibroblasts can also initiate epithelial tumors. Many of these tumors result from the alteration of paracrine growth factor pathways that act on the epithelia. However, the tissue specificity of the responses to the growth factors is a mystery not yet solved.

Introduction

Carcinomas are malignant neoplasms derived from epithelial cells, and represent the most common form of human cancer. A specialized stroma accompanies carcinomas, and is characterized by modifications in the non-epithelial cell types that secrete extracellular matrix (ECM) proteins and growth factors. Similar to the stromal cells in normal epithelial tissue, these specialized stromal cells include inflammatory cells (lymphocytes, macrophages and mast cells), fibroblasts and those cells comprising the vasculature. Moreover, just as genetic mutations in the epithelia result in altered rates of apoptosis and proliferation, in addition to changes in morphogenesis, the carcinoma cells in turn promote angiogenesis, increased inflammatory cell recruitment, altered ECM expression and accelerated fibroblast proliferation 1., 2., 3., 4.. Recent reports suggest a role for inflammation, ECM and stromal fibroblasts in the initiation and progression of carcinomas.

In this review, we examine the concept of the co-evolution of the epithelial cancer cell with its associated stroma. It is understood that there is a reciprocal relationship between the epithelia and the stroma in normal tissues, and the mechanisms for this interaction in cancer have been elucidated more recently.

Section snippets

Epithelial interactions with the stroma

The role of the ECM in tumorigenesis includes effects on epithelial polarity and angiogenesis [2]. Together, the cells of the stroma and epithelia regulate the expression and remodeling of the ECM 5., 6., 7.. The basement membrane separates the epithelial and endothelial cells from the stromal components. Inflammatory cells and fibroblasts express the stromal ECM proteins. However, the basal epithelia, myoepithelia and fibroblasts express the major components of the basement membrane (collagen

Impact of stromal cells on the epithelia

The genetic basis of carcinogenesis involves a process of acquiring multiple genetic mutations in epithelial cells [13], resulting in an activated stroma 3., 4.. This specialized stroma has an abundance of inflammatory cells and activated fibroblasts that both express ECM and growth factors to support the survival and proliferation of carcinoma cells in a paracrine fashion.

The mechanism of the long-recognized relationship between inflammation and cancer is emerging [1]. Chronic inflammation can

Mediators of the stromal signals

Carcinoma cells often show enhanced expression of growth factors and the regulators of growth factor effects. The stromally expressed MMPs, elevated in tumors, have diverse roles in growth-regulation, angiogenesis, metastasis and promotion of epithelial transformation [17]. Some of the signals are mediated through the activation of growth factors 17., 18.. Additionally, given that many growth factor pathways have common signaling pathways, a mutation involving a signaling protein can

Conclusions

Recent data bring prominence to the idea of a role for tumor stromal environment as a leading player, and not just a supporting extra, in the initiation of carcinomas. Mutations in stromal cells that specifically regulate paracrine growth factor expression initiate epithelial cancers. Elevated expression of morphogens, anti-apoptotic and proliferative factors in the microenvironment are potential causes of epithelial mutations that lead to transformation. The sensitivity of the epithelial cells

References and recommended reading

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

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work was supported by a DOD USAMRMC grant (to NAB), NIH grants (to HLM), and the Vanderbilt-Ingram Cancer Center Support Grant.

Glossary

Cre-lox
A method, developed in the early 1990s, to enable the selective deletion of specific DNA fragments. Cre enzyme binds to and cuts loxP sites flanking the region of interest, and splices together the remaining DNA.

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