Chemoattractant For Monocytes

The search for tumor-derived monocyte chemoattractants coincided temporally with the more general search for leukocyte-specific chemotactic factors that resulted in the discovery of chemokines. In the early 1980s, Mantovani and colleagues (33) demonstrated that tumor cells in culture secreted monocyte-specific chemoattractant activity that correlated with the extent of monocyte infiltration when these cells formed tumors in vivo. This observation indicated the possibility that infiltrating monocytes were attracted by the tumors themselves rather than by an associated T-cell-dependent immune response, and suggested the existence of a tumor-derived chemotactic factor, as anticipated by Russell (7). A similar correlation was found for human ovarian cancer explants (34).

These observations, and the postulated existence of a tumor-derived chemoattractant for monocytes, occurred at about the same time that several groups isolated a novel

Table 1

Tumors and Tumor Cells That Secrete MCP-1

Glioblastoma cell lines (36) Primary glioblastomas (82) Malignant ependymoma (82)

Myelomonocytic leukemia cell lines (THP-1 [37]; HL-60 [83])

Fibrosarcoma cell line (45)

Mammary carcinoma cell line (rat) (66)

Osteosarcoma cell lines (39,84)

Ovarian carcinomas (primary) (85)

Melanoma cell lines (39)

Rhabdomyosarcoma cell lines (39)

Renal cell carcinoma cell lines (murine; RENCA) (86)

Lung cancer cell line (Calu-3) (87)

Primary melanoma (88)

Malignant fibrous histiocytoma explants (89)

monocyte-specific chemotactic factor. The primate form, called smooth muscle cell chemotactic factor, was purified from the medium of baboon aortic smooth muscle cells in culture (35). However, the human version was isolated independently, by two groups, from malignant cell lines: MCP-1 from gliomas, and monocyte chemotactic and activating factor from myelomonocytic leukemia cells (36,37). Later, it became clear that at least part of the activity ascribed to a tumor-derived monocyte chemotactic factor was due to MCP-1 (38,39).

The murine version of MCP-1 had been described several years earlier as the product of a gene whose expression is induced rapidly after the exposure of murine fibroblasts to platelet-derived growth factor (40-42). Human MCP-1 is 76 amino acids in length, and the first 76 amino acids of murine MCP-1 are very similar to the human version. However, murine MCP-1 differs from its human counterpart by the presence of an additional 49 amino acids at the C-terminus that are highly substituted with sialylated O-linked carbohydrate (43). This glycosylated extension does not affect monocyte chemoattractant activity in vitro, since human and murine MCP-1 have identical biologic specific activities in Boyden chamber monocyte chemotaxis assays. It remains to be determined whether or not the C-terminal domain has a distinctive function in vivo that may be lacking in the human form or supplied in trans by another molecule.

The identification and cloning of MCP-1 provided an opportunity to screen tumors for their expression of a bona fide monocyte-specific chemoattractant. Table 1 lists several types of cell lines, tumor explants, and primary tumor tissues that express MCP-1. Although the list appears to be extensive, MCP-1 expression is not a universal property of tumor cells since there are many tumor types that do not express MCP-1, e.g., prostate carcinoma and many lung cancers (44).

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