Correspondence to: Isaiah J. Fidler, DVM, PhD, M. D. Anderson Cancer Center, Department of Cancer Biology, Unit 173, 1515 Holcombe Blvd., Houston, TX 77030 (e-mail: ifidler{at}mdanderson.org).
The major cause of death from cancer is metastases that are resistant to conventional therapies (1). The pathogenesis of metastasis is dynamic and complex and consists of a series of many interrelated steps. To produce a clinically relevant lesion, metastatic cells must complete all of the following steps: 1) After the initial transformation event, continuous proliferation of tumor cells takes place. 2) This progressive growth of neoplasms requires vascularization. The synthesis and secretion of several angiogenic factors by some tumor cells play key roles in this process. The genetic instability of neoplastic cells in general and metastatic cells in particular leads to the generation of biological heterogeneity. 3) Some tumor cells gain motility, after which 4) they locally invade the host stroma and 5) enter the circulation by means of several nonmutually exclusive mechanisms. 6) Detachment and 7) embolization of small tumor cell aggregates occurs next, but almost all circulating tumor cells are rapidly destroyed by the shear forces generated in the vasculature. 8) Tumor cells that survive the circulation must be arrested in the capillary beds of organs if they are to proceed to the next step of metastasis. 9) Extravasation must occur next, probably by the same mechanisms that influence initial invasion. 10) Proliferation within the vasculature or the organ parenchyma is necessary to complete the metastatic process. If a disseminating tumor cell fails to complete any one of these steps, it will fail to produce a metastasis. The outcome of the process of metastasis is dependent on the interaction between the intrinsic properties of the tumor cells and various host factors, the balance of which varies from patient to patient (13).
In this issue of the Journal, Azuma et al. (4) describe how transforming growth factor (TGF-
) inhibits tumor cell invasion into host tissues, thus inhibiting the subsequent dissemination of tumor cells and production of metastases. Members of the TGF-
superfamily transmit their signals through Smad proteins (57). Smad7 inhibits intracellular signaling by the TGF-
superfamily proteins by binding to corepressors. In a series of elegant experiments, Azuma et al. (4) took advantage of this process and demonstrated that inhibition of TGF-
signaling by an adenovirus-mediated Smad7 gene transfer system in cultured tumor cells and in an in vivo mouse model of breast cancer inhibits the invasive phenotype of tumor cells. Their data therefore implicate TGF-
in the process of invasion and, hence, metastasis.
To reach lymphatics and/or blood vessels, tumor cells must penetrate the host stroma. Three nonmutually exclusive mechanisms are involved in tumor cell invasion of tissues. First, mechanical pressure can force cords of tumor cells along tissue planes of least resistance (8,9). Second, invasive tumor cells secrete a variety of enzymes that can degrade the basement membrane and facilitate their penetration into tissues and blood vessels (3,10,11). To accomplish this, tumor cells must first attach to extracellular matrix (ECM) components by interactions between receptors on the surface of the tumor cells and ligands in the ECM. A prime example of such cell surface receptors is the integrins, which specifically bind cells to laminin, collagen, or fibronectin (12). After binding, tumor cells then degrade connective tissue ECM and basement membrane components using enzymes such as type IV collagenase (i.e., gelatinase, matrix metalloproteinase) and heparinase. In fact, the production of these enzymes in metastatic tumor cells is associated with the invasive capacity of murine and human carcinoma cells (3). The third mechanism is increased tumor cell motility. Most tumor cells possess the necessary cytoplasmic components for active locomotion. Increased motility of tumor cells is preceded by the loss of cellcell cohesive forces (13,14) and decreased expression of E-cadherin, a cell surface glycoprotein involved in calcium-dependent homotypic cellcell cohesion (1316).
E-cadherin is localized at the epithelial junction complex and is responsible for the organization, maintenance, and morphogenesis of epithelial tissues (16,17). Reduced levels of E-cadherin are associated with a decrease in cellular/tissue differentiation and increased grade in human carcinomas (16). Many differentiated carcinomas express levels of E-cadherin messenger RNA that are similar to those of adjacent normal epithelial cells, whereas poorly differentiated carcinomas do not (17,18). Mutations in the E-cadherin gene (19) and abnormalities of the E-cadherinassociated protein -catenin are associated with the transition of cells from the noninvasive to the invasive phenotype (20). Moreover, transfection of an E-cadherinencoding complementary DNA into invasive cancer cells has been shown to alter cytoskeletal elements, thereby inhibiting their motility (21). Azuma et al. (4) report that Smad7 expression increased the expression of E-cadherin and occludin, a component of tight junctions, thus enhancing the cohesive properties of mouse mammary carcinoma cells through formation of adherens junctions and tight junctions in the cancer cells. This reduced motility of the tumor cells inhibited their invasive capability and prevented the cells from proceeding along the metastatic chain of events.
The data presented by Azuma et al. clearly indicate that the inhibition of TGF- by Smad7 is effective only during the early stages of metastasis formation. Systemic administration of the Smad7 adenovirus to mice 3 weeks after the injection of tumor cells only decreased the number of lung and liver metastases compared with untreated control mice. The authors correctly concluded that "Smad7 expression inhibits the development of new metastatic colonies but does not influence the growth or progression of existing metastatic colonies." These data, however, are in variance with the final conclusion by Azuma et al. (4), that "systemic expression of Smad7 may be a novel strategy for the prevention of cancer metastasis, especially among patients with advanced-stage disease." Patients with advanced-stage disease already have well-established metastases for which the inhibition of tumor cell motility is unlikely to produce therapeutic results.
In any event, the pathogenesis of a metastasis consists of a sequence of linked steps. Interruption of the process at any of the steps is likely to eliminate tumor cells from completing the process. Inhibition of tumor cell motility by expression of Smad7 breaks the link of motility in the chain of metastasis. Breaking a link in the metastatic chain inhibits the formation of metastasis.
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