Production of matrix-degrading enzymes determined by tumor implantation site.

An enduring mystery in cancer cell biology is why a given tumor type shows a preference for lymphatic versus hematogenous migration patterns and what factors dictate the tissues in which its metastatic tumor colonies will form. In recent years, investigators have identified a number of variables: 1) anatomy, which determines the location of the next available capillary bed; 2) formation of emboli, resulting in lodging of tumor cells in a given capillary bed; 3) presence of lectins or adhesion molecules (eg, fibronectins and laminins) that specify attachment to particular cells or to extracellular matrix molecules that are tissue specific; 4) presence or absence of local growth factors; and 5) local matrix chemistries affecting tumor growth. The article by Nakajima and associates in this issue of the Journal (7) is the first to show a new variable: the effect of the local environment on the production of matrix-degrading enzymes by tumor cells. The authors showed that human colorectal carcinomas metastasized to liver and lymph nodes in athymic nude mice only if they were injected intracecally and not if they were inoculated subcutaneously. Moreover, the tumor cells in the intracecal location produced dramatically higher levels of heparanase and a 92-kd and a 64-kd species of type IV collagenase, enzymes documented to be critically associated with metastases. What tissue variables could be controlling the production of these matrix-degrading enzymes? Metalloproteinases and the type IV collagenases are not constitutively produced but are transcriptionally regulated by cytokines like interleukin-1, by phorbol esters, and by growth factors such as epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) (for review, see ref 2). The tissue-destructive potential of these enzymes requires a tight regulation of their secretion and quick inactivation once their remodeling effects have been completed. Two recently identified tissue inhibitors of metalloproteinases inhibit both the 92-kd and the 64-kd collagenase type IV enzymes {3,4). Experimentally, these inhibitors have been shown to be involved in tumor invasion. Inactivation of these inhibitors by transfection of their anti-sense strand molecules has rendered the tumor cells highly invasive; in contrast, high levels of endogenous tissue inhibitors of metalloproteinases can prevent the tumor invasion that occurs in cirrhotic livers (5). Nakajima and colleagues found that the expression of these inhibitors was similar in the tumors grown at both the subcutaneous and intracecal locations. Thus, the distinction in the production of the matrix-degrading enzymes between the subcutaneous versus the intracecal location could not be attributed to regulation of these inhibitors. The authors speculate that local growth factors could be responsible for their observations. The growth factors could be soluble and produced locally, they could be cytokines produced by local lymphocytes and macrophages; or they could be factors that are made insoluble and stable by association with the local extracellular matrix, such as basic fibroblast growth factor (bFGF), which is known to be bound into basement membranes (6). An alternative not considered by the authors is that the matrix chemistry could modulate enzyme production. The matrix chemistry has already been documented to be tissue specific and to have tissue-specific effects on tumor growth, either directly or via stimulation of growth factor production (7). Perhaps these differential effects of particular matrix chemistries on tumor growth are achieved by regulation of enzyme production. The data from this study identify a new variable affecting organ-site specificity of metastasis and suggest new assays predictive of metastatic potential: assays for organ-specific regulators of matrix-degrading enzymes produced by tumor cells. Identification of these regulators and characterization of their mechanisms of action will be important in the development of new and rational therapies for metastases.