Mechanisms Of Mcp1 Antitumor Effects

There is now a preponderance of evidence that MCP-1 can contribute to host antitumor activity, but there are strikingly few data on the mechanism. Efficacy in nude mouse models indicates that the effect of MCP-1 is not T-lymphocyte dependent, but there are no data to indicate what the effector cell might be (i.e., monocyte vs NK cell) or whether MCP-1 is necessary for effector cells to suppress tumor growth. In other words, MCP-1 might attract effector cells as it attracts monocytes in transgenic models, but it may not be required to activate antitumor function. What few data there are can be summarized as follows.

In an early study, the addition of MCP-1 to purified human monocytes in tissue culture enhanced their ability to inhibit DNA synthesis in six malignant human cell lines (37). These included colon and breast carcinoma lines as well as melanoma, rhab-domyosarcoma, and leiomyosarcoma lines. The effect was clearly cytostatic and occurred with an ED50 of approx 0.3 nM, consistent with MCP-1's Kd for its receptor on monocytes.

By contrast, the ability of MCP-1 to enhance the tumoricidal effects of monocytes in vitro has been documented (71). Elicited peritoneal macrophages from C3H mice were incubated with radiolabeled syngeneic murine melanoma cells (K-1735) at an effector:target ratio of 10:1. In the presence of 1 ^g/mL of LPS, macrophages were able to lyse melanoma cells engineered to express human MCP-1, but not parental or control cells. (LPS plus interferon-y induced lysis regardless of MCP-1 expression status.) The addition of LPS and human MCP-1 to cultures of macrophages induced lysis of non-MCP-1-expressing melanoma cells, indicating that MCP-1 secretion by the engineered cells was responsible for activating macrophage antitumor activity. Identical results were obtained in another mouse strain (Balb/c) using syngeneic colon carcinoma cell lines and murine MCP-1 (67). These tantalizing data suggest the possibility of synergistic effects between MCP-1 and other agents to induce macrophage tumoricidal activity. However, the relevance of this precise effect has yet to be demonstrated in vivo.

An alternative approach to using MCP-1 was demonstrated by transfecting an MCP-1 cDNA into small-cell lung cancer cell lines that express P-glycoprotein (72). As in other systems, MCP-1 did not alter the growth rate of these cells in vitro, but in this model, MCP-1 expressers formed tumors in nude mice with the same efficiency and growth rate as control cells. However, the tumor-suppressive effects of systemi-cally administered anti-P-glycoprotein antibody were much greater against the MCP-1-expressing cells. This suggests that even when MCP-1-mediated macrophage attraction is insufficient to produce tumor cell death, the presence of MCP-1 can enhance antibody-dependent cellular cytotoxicity. (The MCP-1 effect is probably related to macrophage elicitation in vivo since the addition of recombinant MCP-1 to mixed macrophage/tumor cell cultures in vitro did not enhance cytotoxicity.)

Finally, there is the demonstration cited previously that MCP-1 can enhance immunologically specific antitumor responses (70). This could simply be a result of the ability of MCP-1 to attract macrophages (or dendritic cells) to a tumor. Enhanced antigen presentation or T-lymphocyte costimulation could be due to other local influences.

How To Prevent Skin Cancer

How To Prevent Skin Cancer

Complete Guide to Preventing Skin Cancer. We all know enough to fear the name, just as we do the words tumor and malignant. But apart from that, most of us know very little at all about cancer, especially skin cancer in itself. If I were to ask you to tell me about skin cancer right now, what would you say? Apart from the fact that its a cancer on the skin, that is.

Get My Free Ebook

Post a comment