Review
Stromagenesis: The changing face of fibroblastic microenvironments during tumor progression

https://doi.org/10.1016/j.semcancer.2005.05.003Get rights and content

Abstract

During tumorigenesis, reciprocal changes in stromal fibroblasts and tumor cells induce changes to the neoplastic microenvironmental landscape. In stromagenesis, both the complex network of bi-directional stromal fibroblastic signaling pathways and the stromal extracellular matrix are modified. The presence of a ‘primed’ stroma during the early, reversible stage of tumorigenesis is optimal for stromal-directed therapeutic intervention. Three-dimensional (3D) cell culture systems have been developed that mimic the in vivo microenvironment. These systems provide unique experimental tools to identify early alterations in stromagenesis that are supportive of tumor progression with the ultimate goal of blocking neoplastic permissiveness and restoring normal phenotypes.

Section snippets

Stroma: the tumor microenvironment

The traditional concept that cells immediately adjacent to a tumor are passive structural elements that elicit an immune response in an attempt to resist and reject the tumor has now been challenged by a considerable body of evidence from many investigators [1]. Here, we review the evidence that contrary to being an idle bystander, the surrounding tumor microenvironment or ‘stroma’, actively participates in, and contributes to tumor progression. Interestingly, the first hint that the tumor

Normal stromal microenvironment: a protective barrier that suppresses tumor progression

Under normal physiologic conditions, fibroblasts have a low proliferative index and only secrete factors needed to maintain normal tissue homeostasis [3]. Indeed, normal fibroblasts provide biochemical cues to constrain epithelial tumor cells within their basement membrane; the specialized matrix required to maintain epithelial polarity. During early hyperplasia, when epithelial cells have started to proliferate, the basement membrane is able to confine an early tumor cell clone until this

Primed stroma: early stage fibroblasts and their ECMs can be reversibly modified, yet provide an inductive and permissive terrain for emerging tumor cells

Changes in stromal characteristics are an initial attempt to ‘repair the damage’ induced by the transformed epithelium. A complex interplay of reciprocal stromal–epithelial interactions that originate with tumor progression, essentially fool the repair mechanisms towards stromagenesis [3]. In fact, the ‘tissue organization field theory’ proposes that carcinogenesis results from the loss or breakdown of biological organization induced by perturbed stromal–epithelial interactions, rather than

Crosstalk between tumor and stromal fibroblasts

A four-stage process has been proposed for melanoma stromagenesis: (1) recruitment of resident dermal fibroblasts or circulating precursor cells; (2) fibroblast activation and proliferation; (3) myofibroblast differentiation; and (4) further differentiation into fibrocytes while synthesizing a tumor-permissive ECM [48]. The tumor cell-derived factors transforming growth factor-β (TGFβ), basic fibroblast growth factor (bFGF), platelet-derived growth factor (PDGF), and vascular endothelial growth

Experimental model systems for tumor–stroma interactions: creating an in vivo-like microenvironment

From the considerable body of literature studying tumor–stromal interactions in vivo, it is clear that tumor progression involves complex interactions between stromal and tumor compartments. To sort out these complexities, investigators have turned to in vitro culture systems to gain insights into the mechanisms that control normal differentiation and aberrant mechanisms that induce tumorigenesis when regulatory controls have gone awry [13]. Moreover, during stromagenesis, fibroblast-induced

Spheroids: 3D cultures of multiple cell types

In addition to having the appropriate mechanical properties and three-dimensionality, a physiologically relevant in vitro 3D culture system must also reflect the cellular and molecular composition of the in vivo microenvironment [14], [22]. Spheroids represent a 3D culture system of tumor cell biology that can assess tumor–stromal interactions by co-culture with multiple cell types [5], [75]. Spheroid co-cultures of tumor-stromal fibroblasts and tumor-endothelial cells are used to understand

Acknowledgements

Our primary intention in this review is to present an overview of a vast body of literature within the constraints of the space provided. If we have inadvertently omitted specific studies in this review, their omission does not diminish their significance. The authors thank Drs. J.D. Cheng and D. Bassi for their helpful suggestions and comments, Mrs. K. Buchheit for the assertive proof-reading of this manuscript, and Mr. M.D. Amatangelo for the exceptional technical assistance. This work is

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