JOURNALOF PATHOLOGY, VOL.
161: 187-188 (1990)
EDITORIAL MONOCYTE CHEMOATTRACTANTS PRODUCED BY MALIGNANT CELLS Macrophages have the potential to dramatically to SMC-CF. Serum free medium conditioned by influence the behaviour of tumour cells. Macro- MG-63 cells was tested for stimulation of monocyte phages may stimulate tumour growth through the migration and for the capacity of SMC-CF antiproduction of proliferative and angiogenic factors serum to block this activity. Antiserum to SMC-CF or exert an inhibitory affect through the production blocked all of the monocyte chemotactic activity of factors such as interferon, tumour necrosis factor secreted by the MG-63 osteosarcoma cell line, and transforming growth factor-beta. Tumours demonstrating that proteins related to SMC-CF are often infiltrated by macrophages, which fre- are the predominant monocyte chemoattractants quently constitute 20-30 per cent of the cellular mass produced by these cells in vitro. The above observations were extended to other of a solid tumour. The macrophage content of tumours is sustained through the recruitment of cir- tumour cell lines, as well as to primary osteoculating monocytes, which undergo maturation in sarcoma cell cultures.6 Thirteen different human situ to macrophages and by the local proliferation of malignant cell cultures were tested. Nine of these macrophages. The recruitment of monocytes in- synthesized detectable levels of SMC-CF-like provolves the generation of chemotactic factors that teins, as determined by immunoprecipitation with initiate migration toward the tumour. This was SMC-CF antiserum but not by control serum. demonstrated by Bottazzi and co-workers who These included one cell line derived from a melareported that tumour infiltration by macrophages noma, two cell lines derived from glioblastoma, in animals was correlated with the production of a fibrosarcoma, a rhabdomyosarcoma, and two monocyte chemoattractants by the tumours in ~ i t t - 0 . ~different osteosarcoma cell lines, as well as two A number of chronic inflammatory states are primary osteosarcoma cell cultures. All of the associated with monocyte infiltration. One of these is malignant cell cultures that synthesized SMC-CF atherosclerosis,which is characterized by the recruit- related proteins produced high levels of chemotactic ment of peripheral blood monocytes to the arterial activity that was inhibited by SMC-CF antisera. intima in the early lesion. In the process of studying Four cell lines did not synthesize SMC-CF-like prorecruitment of monocytes to the vascular wall, a teins and were derived from a bladder carcinoma, monocyte chemoattractant produced by smooth epidermoid carcinoma, leiomyosarcoma, and an muscle cells was identified, smooth muscle cell- osteosarcoma. Significantly,the four cell lines tested derived chemotactic factor (SMC-CF).’ SMC-CF is that did not synthesize SMC-CF-like proteins also asmall(I4.5 kD),singIechainprotein thatstimulates did not produce large amounts of chemotactic acchemotactic activity in monocytes, but not in tivity. Thus, a correlation was observed between the lymphocytes or polymorphonuclear leukocytes. production of SMC-CF-like proteins and producHuman malignant cells have been shown to pro- tion of monocyte chemoattractants. That virtually duce monocyte chemotactic activity that has bio- all of the monocyte chemotactic activity could be chemical properties similar to SMC-CF. In order blocked by SMC-CF antiserum suggests that SMCto investigate the relationship between the mono- CF-like factors represent the predominant chemocyte chemotactic factors produced by malignant tactic factor produced by tumour cells in vitro. cells and vascular smooth muscle, immunochemical These data also suggest that tissue origin of transstudies were undertaken using an antibody specific formed cells does not determine whether significant to SMC-CF.~Immunoprecipitation experiments amounts of SMC-CF-like proteins are produced. SMC-CF-like proteins appear to be responsible using SMC-CF antiserum demonstrated that the MG-63 human osteosarcoma cell line synthesizes for most, if not all of the non-latent monocyte and secretes a protein that is antigenically related chemotactic activity produced by several different 0022-3417/90/070187-02 $05.00 0 1990 by John Wiley & Sons, Ltd.
188
EDITORIAL
malignant cell cultures in vitro. This may be of considerable importance in vivo due to the potential of monocytes/macrophages to regulate tumour growth as evidenced by the capacity of the latter to secrete factors that either enhance or inhibit the proliferation of neoplastic cells. Macrophages may also secondarily affect the behaviour of tumours through the production of angiogenesis factors that increase vascular support for tumour growth, or may produce factors and enzymes that have the potential to affect tumour cell invasion, metastasis, or exert tumouricidal From the studies reported here it is apparent that tumour cells are capable of producing monocyte chemoattractants related to SMC-CF that have the potential to induce the migration of blood borne monocytes into neoplastic tissue. Thus a single class of proteins produced by non-transformed vascular smooth muscle cells, as well as several different malignant cell types, is responsible for the secreted monocyte chemotactic activity. This suggests a common mechanism for the recruitment of monocytes/macrophages and provides an explanation for monocyte/macrophage infiltration frequently observed in solid tumours. The observation that SMC-CF is virtually identical to the monocyte chemotactic protein-1 (MCP-1) further substantiates the hypothesis that SMC-CF/ MCP-1 is an important inflammatory mediator in-
volved in the recruitment of monocytes in tumours and in other pathologic condition^.^,'
DANA GRAVES Boston University Medical Center Boston, Massachusetts, U .S .A . AND ANTHONY VALENTE Cleveland Research Institute Cleveland, Ohio, U.S.A.
REFERENCES RB.Current concepts: immunology, monocytes and macrophages. New Eng J Med 1988; 318 747-751. 2. Carswell EA, Old U,Kassel RL, Green S,Fiore N, Williamson B. An endotoxin-induced strum factor that causes necrosis of tumors. Pror Nail AcadSci USA 1975; I 2 3666-3670. 3. McBride WH.Phenotype and functions of intratumoral macrophages. Biochem 5ioph.v~Acta 1986; 865:27-41. 4. BotcaPi B, Polentarutti N, Acero R, er a/. Regulation of the macrophage content of neoplasms by chernoattractants, Science 1983; 2 2 0 2 I &2 12. 5. Valente AJ, Graves DT, Vialle-Valentin CE. Delgado R. Schwartz CJ. Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular e l l s in culture. Biochemistry 1988; 27: 4162-4168. 6. Graves DT, Jiang YL, Williamson MJ. Valente AJ, Identification of monocyte chemotactic activity produced by malignant cells. Science 1989; 345:149C-1493. 7. Robinson EA, Yoshimura T, Leonard EJ. e r a / . Complete amino acid sequence of a human monocyte chemoattractant. a putative mediator ofcellular immune reactions. Proc Nor/ Acad Sci U S A 1989 86: 1850I. Johnston
1854.
161: 187-188 (1990)
EDITORIAL MONOCYTE CHEMOATTRACTANTS PRODUCED BY MALIGNANT CELLS Macrophages have the potential to dramatically to SMC-CF. Serum free medium conditioned by influence the behaviour of tumour cells. Macro- MG-63 cells was tested for stimulation of monocyte phages may stimulate tumour growth through the migration and for the capacity of SMC-CF antiproduction of proliferative and angiogenic factors serum to block this activity. Antiserum to SMC-CF or exert an inhibitory affect through the production blocked all of the monocyte chemotactic activity of factors such as interferon, tumour necrosis factor secreted by the MG-63 osteosarcoma cell line, and transforming growth factor-beta. Tumours demonstrating that proteins related to SMC-CF are often infiltrated by macrophages, which fre- are the predominant monocyte chemoattractants quently constitute 20-30 per cent of the cellular mass produced by these cells in vitro. The above observations were extended to other of a solid tumour. The macrophage content of tumours is sustained through the recruitment of cir- tumour cell lines, as well as to primary osteoculating monocytes, which undergo maturation in sarcoma cell cultures.6 Thirteen different human situ to macrophages and by the local proliferation of malignant cell cultures were tested. Nine of these macrophages. The recruitment of monocytes in- synthesized detectable levels of SMC-CF-like provolves the generation of chemotactic factors that teins, as determined by immunoprecipitation with initiate migration toward the tumour. This was SMC-CF antiserum but not by control serum. demonstrated by Bottazzi and co-workers who These included one cell line derived from a melareported that tumour infiltration by macrophages noma, two cell lines derived from glioblastoma, in animals was correlated with the production of a fibrosarcoma, a rhabdomyosarcoma, and two monocyte chemoattractants by the tumours in ~ i t t - 0 . ~different osteosarcoma cell lines, as well as two A number of chronic inflammatory states are primary osteosarcoma cell cultures. All of the associated with monocyte infiltration. One of these is malignant cell cultures that synthesized SMC-CF atherosclerosis,which is characterized by the recruit- related proteins produced high levels of chemotactic ment of peripheral blood monocytes to the arterial activity that was inhibited by SMC-CF antisera. intima in the early lesion. In the process of studying Four cell lines did not synthesize SMC-CF-like prorecruitment of monocytes to the vascular wall, a teins and were derived from a bladder carcinoma, monocyte chemoattractant produced by smooth epidermoid carcinoma, leiomyosarcoma, and an muscle cells was identified, smooth muscle cell- osteosarcoma. Significantly,the four cell lines tested derived chemotactic factor (SMC-CF).’ SMC-CF is that did not synthesize SMC-CF-like proteins also asmall(I4.5 kD),singIechainprotein thatstimulates did not produce large amounts of chemotactic acchemotactic activity in monocytes, but not in tivity. Thus, a correlation was observed between the lymphocytes or polymorphonuclear leukocytes. production of SMC-CF-like proteins and producHuman malignant cells have been shown to pro- tion of monocyte chemoattractants. That virtually duce monocyte chemotactic activity that has bio- all of the monocyte chemotactic activity could be chemical properties similar to SMC-CF. In order blocked by SMC-CF antiserum suggests that SMCto investigate the relationship between the mono- CF-like factors represent the predominant chemocyte chemotactic factors produced by malignant tactic factor produced by tumour cells in vitro. cells and vascular smooth muscle, immunochemical These data also suggest that tissue origin of transstudies were undertaken using an antibody specific formed cells does not determine whether significant to SMC-CF.~Immunoprecipitation experiments amounts of SMC-CF-like proteins are produced. SMC-CF-like proteins appear to be responsible using SMC-CF antiserum demonstrated that the MG-63 human osteosarcoma cell line synthesizes for most, if not all of the non-latent monocyte and secretes a protein that is antigenically related chemotactic activity produced by several different 0022-3417/90/070187-02 $05.00 0 1990 by John Wiley & Sons, Ltd.
188
EDITORIAL
malignant cell cultures in vitro. This may be of considerable importance in vivo due to the potential of monocytes/macrophages to regulate tumour growth as evidenced by the capacity of the latter to secrete factors that either enhance or inhibit the proliferation of neoplastic cells. Macrophages may also secondarily affect the behaviour of tumours through the production of angiogenesis factors that increase vascular support for tumour growth, or may produce factors and enzymes that have the potential to affect tumour cell invasion, metastasis, or exert tumouricidal From the studies reported here it is apparent that tumour cells are capable of producing monocyte chemoattractants related to SMC-CF that have the potential to induce the migration of blood borne monocytes into neoplastic tissue. Thus a single class of proteins produced by non-transformed vascular smooth muscle cells, as well as several different malignant cell types, is responsible for the secreted monocyte chemotactic activity. This suggests a common mechanism for the recruitment of monocytes/macrophages and provides an explanation for monocyte/macrophage infiltration frequently observed in solid tumours. The observation that SMC-CF is virtually identical to the monocyte chemotactic protein-1 (MCP-1) further substantiates the hypothesis that SMC-CF/ MCP-1 is an important inflammatory mediator in-
volved in the recruitment of monocytes in tumours and in other pathologic condition^.^,'
DANA GRAVES Boston University Medical Center Boston, Massachusetts, U .S .A . AND ANTHONY VALENTE Cleveland Research Institute Cleveland, Ohio, U.S.A.
REFERENCES RB.Current concepts: immunology, monocytes and macrophages. New Eng J Med 1988; 318 747-751. 2. Carswell EA, Old U,Kassel RL, Green S,Fiore N, Williamson B. An endotoxin-induced strum factor that causes necrosis of tumors. Pror Nail AcadSci USA 1975; I 2 3666-3670. 3. McBride WH.Phenotype and functions of intratumoral macrophages. Biochem 5ioph.v~Acta 1986; 865:27-41. 4. BotcaPi B, Polentarutti N, Acero R, er a/. Regulation of the macrophage content of neoplasms by chernoattractants, Science 1983; 2 2 0 2 I &2 12. 5. Valente AJ, Graves DT, Vialle-Valentin CE. Delgado R. Schwartz CJ. Purification of a monocyte chemotactic factor secreted by nonhuman primate vascular e l l s in culture. Biochemistry 1988; 27: 4162-4168. 6. Graves DT, Jiang YL, Williamson MJ. Valente AJ, Identification of monocyte chemotactic activity produced by malignant cells. Science 1989; 345:149C-1493. 7. Robinson EA, Yoshimura T, Leonard EJ. e r a / . Complete amino acid sequence of a human monocyte chemoattractant. a putative mediator ofcellular immune reactions. Proc Nor/ Acad Sci U S A 1989 86: 1850I. Johnston
1854.
