A strong desmoplastic reaction is a common aspect of many solid tumors, including those of the breast, prostate, colon, and lung. This reaction represents a peculiar phenotypic change due to a morphologically and functionally altered stroma frequently associated with inflammatory cells. TGF-β, present in a latent form in the ECM and often produced by tumor cells, and platelet-derived growth factor (PDGF), a potent mitogen and chemoattractant for mesenchymal cells, are two reasonable candidates for involvement in the induction of the desmoplastic response through different signaling routes (Elenbaas and Weinberg, 2001; Tlsty, 2001). Ultrastructural and immunohistochemical analyses support the notion that typical markers of the desmoplastic reaction are altered expression levels of α-smooth-muscle actin, smooth muscle myosin, vimentin and desmin in desmoplastic fibroblasts (Sappino et al., 1990), and altered production of several ECM proteins such as collagen types III, V, and tenascin (Sappino et al., 1990), laminin (Tagliabue et al., 1996), MMPs and their inhibitors (Chang and Werb, 2001), and growth factors (Nakamura et al., 1997). Additionally, the distribution and expression levels of laminin, a molecule critical for the architectural integrity of tissue, is altered and reduced in fibroblasts associated with malignant cells (Tlsty, 2001). Recent studies using a gene expression profiling technique, have shown that the gene for osteopontin a secreted integrin-binding ECM glycoprotein, is differentially expressed during colon cancer progression (Agrawal et al., 2002). In keeping, we found that glycoprotein fibulin-1 (FBLN-1), a cysteine-rich, calcium-binding ECM and plasma molecule (Argraves et al., 1990), is aberrantly overtranscribed in epithelial tumor cell lines and breast surgical specimens, and that the protein is accumulated in the breast cancer-associated stroma, as detected immunohistochemically (Forti et al., 2002). Augmented expression of FBLN-1 has been also reported in human ovarian cancer cells stimulated with estrogens, and the resulting overexpression facilitated ovarian tumor cell invasion and progression (Clinton et al., 1996; Moll et al., 2002). FBLN-1 self-associates and binds to other ECM proteins, including fibronectin, laminin and nidogen, and to fibrinogen (Roark et al., 1995). Since FBLN-1 under physiological conditions participates to laminin polymerization, its excess in ECM might induce disruption of laminin polymers, in turn changing the signal mediated by the interaction of tumor cells with ECM. FBLN-1 might also promote tumor cell extravasation, since this protein has been shown to increase platelet adhesion by interacting with fibrinogen (Tran et al., 1995). By analysis of recombinant cDNA expression library using breast cancer patients' sera, we detected humoral immunity to FBLN-1 (Forti et al., 2002), indicating that altered ECM components can also be immunogenic in tumor patients.
Hyaluronic acid (HA), an ECM polysaccharide involved in wound healing by promoting cell migration through its cell surface receptor, is also frequently overexpressed in malignant tumors. The intensity of HA in the stroma was found to be an independent prognostic factor for overall survival according to Cox's multivariate analysis (Auvinen et al., 2000). HA interacts with tumor cells through the hyaluran-binding protein RHAMM by which it regulates ras signaling. Accordingly, RHAMM expression has been associated with lymph node metastasis (Wang et al., 1998).
Recent studies suggest that oncogenic activity displayed by stroma can reflect many different processes, including: exposure to carcinogens, which not only induce genetic changes in the cell that directly damage the epithelium, but also alter ECM composition; altered growth factor activities, mainly mediated by the pleiotropic cytokine TGF-β, whose effects include phenotypic changes in adhesion, migration, differentiation and cell death, and altered expression of receptors that mediate cell–cell interactions (Barcellos-Hoff and Ravani, 2000); and direct cellular communications with the ECM, especially β1-integrins (Ruoslahti, 1999). Together, these findings point to the significant contribution of stromal alterations to tumorigenesis.
As a potentially oncogenic agent, the stroma can drive tumorigenicity in adjacent cells with the acquisition of genomic changes and in the absence of pre-existing tumor cells. As a physically supportive and responsive structure, the stroma can be induced by tumor cells to express critical signals that drive proliferation, angiogenesis, and motility and that suppress apoptosis.