PerspectiveCANCER

Respect Thy Neighbor!

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Science  06 Feb 2004:
Vol. 303, Issue 5659, pp. 775-777
DOI: 10.1126/science.1094412

The complexity of multicellular organisms necessitates a high degree of coordination among a diverse range of specialized cell types. Maintaining this organization requires a constant and dynamic stream of intercellular communication. Increasing evidence suggests that this organized exchange of information is essential for maintaining the differentiated state of cells, and that sustained disruption of key intercellular signaling pathways can predispose to malignancy (1). Epithelial tissue is the source of more than 80% of human cancers, and many studies have focused on identifying the factors that activate signaling pathways involved in the proliferation of epithelial cells. The stromal cells that surround and sustain epithelia have been viewed primarily as a source of oxygen, nutrients, and additional growth stimuli for tumors. However, on page 848 of this issue, Bhowmick et al. (2) report that defective stromal cells stimulate the development of epithelial tumors, which suggests that normal stromal cells may prevent epithelia from becoming tumorigenic. The investigators found that transgenic mice with stromal fibroblasts unable to respond to the cytokine TGF-β (transforming growth factor-β) rapidly developed lethally aggressive cancers derived from the forestomach and prostate epithelium. These results provide insight into the multifaceted roles of TGF-β, and into the larger question of how stromal-epithelial interactions affect the development of epithelial tumors.

It is well established that cellular tumorigenic potential is profoundly influenced by the microenvironment and that malignant cells can be induced to maintain a differentiated state by growth in an appropriate tissue microenvironment [for a review, see (3)]. The classic work of Mintz and colleagues showed that injection of undifferentiated embryonal carcinoma cells into mouse blastocysts suppresses their inherent tumorigenicity, allowing these potentially malignant cells to contribute to a variety of functional tissues in adult mice (4). The highly oncogenic Rous sarcoma virus (RSV) triggers the formation of aggressive tumors in chickens but does not induce tumors when injected into chick embryos (5), a phenomenon later shown to be dependent partly on the integrity of the extracellular matrix (ECM). Some of the antitumorigenic components involved in the protective responses of ECM and stroma have been isolated and are now in clinical trials. Examples include endostatin, an antiangiogenic 20-kD peptide derived from the stromal ECM molecule collagen XVIII (6), and tumstatin, an antiangiogenic and proapoptotic 28-kD peptide derived from collagen IV (7).

Otherwise functional cells can be provoked to become malignant through disruption of stimuli from the microenvironment. Just as a nurturing atmosphere produces harmony, so consorting with disruptive elements wreaks havoc. In RSV-infected chickens, observations that tumors preferentially formed at the site of RSV injection led to the discovery that TGF-β released at the wound site was the tumor-promoting factor (8). In mice, irradiation of stromal cells (which also activates TGF-β) greatly potentiated the tumor-forming ability of transplanted cells (9). Likewise, increased expression in the mammary gland of the ECM-degrading enzyme, matrix metalloproteinase-3, was sufficient to induce mammary tumors (10). In humans, inflammation caused by the gastric pathogen Helicobacter pylori is a major risk factor for the development of gastric cancer (11). Similarly, chronic inflammation caused by the autoimmune disease ulcerative colitis stimulates epithelial cyst formation and progression to tumors (12). In all of these cases, the characteristics of the disrupted microenvironment are quite complex: The cytokine profiles and the tissue architecture become dramatically altered, and remodeling of the ECM is associated with changes in its chemical composition and structural properties. Not surprisingly, progress toward identifying the key mechanisms by which these microenvironmental alterations promote tumors has proved a lengthy endeavor.

Additional insight into stromally induced carcinomas has come from studies of the heritable hamartomatous polyposis diseases. Analysis of the colonic polyps that develop in individuals affected with these syndromes revealed that the loss of genetic function occurs predominantly in mesenchymal fibroblasts (13). These discoveries point to a new class of tumor susceptibility genes that act in the stroma to prevent the formation of epithelial carcinomas—a phenomenon that Kinzler and Vogelstein have called the “landscaper” effect (14). The relevant genetic elements have been the target of intense investigation (15): Juvenile polyposis syndrome is caused by defects in the genes encoding bone morphogenetic protein receptor IA (BMPRIA) or the transcription factor Smad4, and Cowden disease is caused by inactivation of the gene encoding the phosphatase and tensin homolog PTEN. In light of the new work by Bhowmick et al., it is noteworthy that all of these factors are associated with TGF-β (15). BMPRIA is functionally related to the TGF-β signaling pathway in that this receptor transduces its signal through Smad4 (see the figure); PTEN is regulated by these same signal transduction pathways.

The stromal-epithelial connection.

Signaling pathways in stromal cells activated by TGF-β and BMP prevent tumor formation in epithelia. TGF-β signaling can be initiated by association with type III TGF-β receptors prior to formation of an active kinase complex containing receptor types I and II. The active TGF-β signaling complex phosphorylates receptor-regulated R-SMADs such as Smad2 and Smad3, which then bind to common partner co-SMADs such as Smad4. The resulting activated complex can bind to specific DNA sequences and influence the transcription of many tissue-specific genes. Similarly, BMP family members form an active BMP signaling complex, which phosphorylates Smads 1, 5, and 8. These activated R-SMADs then associate with Smad4 to form an active transcriptional complex. Loss of TβRII, Smad4, or BMPRI in stromal cells can stimulate the formation of tumors in adjacent epithelium, although the signals involved in this process have notCREDIT: TAINA LITWAK yet been identified.

Bhowmick et al. describe the phenotype of Tgfbr2fspKO mice, in which TGF-β receptor type II (TβRII) is selectively inactivated in fibroblasts. TGF-β is a cytokine polypeptide that is involved in such physiological processes as differentiation, development, wound healing, and angiogenesis, and it can also act as a tumor suppressor or as a tumor promoter, depending on the context (8, 16). Early development of the Tgfbr2fspKO mice appeared normal, but by 3 weeks of age, there was a rapid increase in the number of stromal fibroblasts in the prostate, followed by epithelial neoplasia, and a similar process was observed in the forestomach. These findings suggest the existence of a TGF-β-induced signaling pathway that is initiated in the stroma and terminates, either directly or indirectly, in epithelial cells. That TGF-β indirectly promotes tumors by stimulating stromal reactivity and fibrosis is well established (17), but the fascinating discovery of Bhowmick et al. is that TGF-β signaling can act as an indirect tumor suppressor. Moreover, the fact that loss of TβRII in stromal fibroblasts leads so quickly and so inexorably to epithelial carcinoma provides a clear counterexample to the assumption that mutations in epithelial cells are the required initiating factors for carcinoma. Thus, far from being a mere “landscaper,” the tissue microenvironment is a powerful regulator of tumor induction as well as tumor suppression—a role that clearly merits not only further exploration, but also respect!

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