211 MACROPHAGES AS TUMOUR GROWTH PROMOTERS? Dr Hamburger’ discuss analoand between B neoplastic cell clonal proliflymphocyte gies eration being stimulated by a macrophage-derived factor(s). Although very interesting, this hypothesis has been oversimplified and based mainly on in-vitro data of colony formation. The theory of immunostimulation of cancer growth has been known for some time ;2 the promotion or inhibition of metastasis formation by sensitised lymphocytes was shown by Fidler in B16 melanoma system;3 and Salmon and Hamburger present the theory of macrophage stimulation of both carcinogentriggered epithelial tumour cell (as second-phase promoter)
SIR,-Professor Salmon and
.
and antigen-triggered B-lymphocyte proliferation. Monocyte-macrophage cells are the predominant source of colony-stimulating factor (c.s.F.) in myelopoiesis, and the same cells, at certain critical c.s.F. concentration, begin production of prostaglandin E which suppresses myelopoiesis.4 Feedback control of excessive myelopoiesis thus operates through the same growth-promoting and growth-inhibiting population of macrophage-like cells. Although the glycoprotein described by Salmon and Hamburger was antigenically dissimilar from the myelopoiesis-stimulating C.S.F., the point is that the same population of cells can demonstrate two diametrically opposite functions, dependent on quantitative differences of c.s.F. concentration. The suppression of B-cell-derived polyclonal humoral antibody production by monocyte-like cells has been shown by Broder et al. in some patients with myeloma. Whether the same cells are capable of stimulating monoclonal B cells in patients with myeloma remains to be established in vivo. The demonstration in vitro that macrophage-derived glycoprotein is also able to stimulate colony-formation of various other neoplastic cells is very intriguing. However, there is abundant evidence from laboratory animal and human systems that macrophage content of the tumour correlates with prognosis and risk of metastatic spread.6-9 Macrophages, although having limited capacity,’O protect to a certain extent against the tumour
spread 6- 10 and, they can selectively kill neoplastic but not normal cells.’Whether the presence of significant numbers of macrophages in malignant effusions represents a cause of rather than a protective response against, tumour growth will have to be established in vivo. Macrophages can produce several other humoral factors which are selectively tumoricidal and definitely do not promote tumour growth.llll2 Although very provocative, the suggestions that macrophages or macrophage-derived humoral factor(s) can promote the monoclonal neoplastic growth and that organ macrophage content can positively correlate with the promotion of tumour growth do contradict well-founded evidence of a protective role of macrophages against neoplastic growth and spread. The potentially beneficial role of macrophages in tumour-growth control has been ignored by Salmon and Hamburger, perhaps for the sake of clear and simplified presentation. It could be that the growth-stimulatory effect of a macrophage-derived factor on a minority of clonogenic cells in vivo counteracts the otherwise inhibitory effect of other macrophage-related factors 1. 2. 3. 4.
Salmon, S. E., Hamburger, A. Lancet, 1978, i, 1289. Prehn, R. T., Lappé, M. A. Transplant. Rev. 1971, 7, 26. Fidler, I. J. Cancer Res. 1974, 34, 491. Kurland, J. I., Bockman, R. S., Broxmeyer, H. E., Moore, M. A. S. Science, 1978, 199, 552. 5. Broder, S, Humphrey, R., Durm, M., Blackman, M., Meade, B., Goldman, C., Strober, W., Waldmann, T. A. New Engl. J. Med., 1975, 293, 887. 6. Eccles, S. A., Alexander, P. Nature, 1974, 250, 667. 7. Evans, R., Alexander, P. ibid., 1972, 236, 168. 8. Schultz, R. M., Papamatheakis, J. D., Stylos, W. A., Chirigos, M. A. Cell. Immun. 1976, 25, 309. 9. Hibbs, J. B., Jr., Lambert, L. H., Jr., Remington, J. S. Nature neō Biol.,
1972, 235, 48. 10. Lancet, 1976, ii, 27. 11. Currie, G. A., Basham, C.J. exp. Med., 1975, 142, 1600. 12. Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., B. Proc nat. Acad Sci. U.S.A., 1975, 72, 3666.
Williamson,
This might limit the capacity of macroinhibit tumour growth. The possibility of imphages elimination of the clonogenic-promoting munologically specific factor(s) and exploration of its properties (e.g., does it demon-
on tumour
growth.
alone
to
angiogenesis-promoting characteristics?") warrant investigation. It is important, even when presenting a hypothesis, to try to encompass all important aspects of the macrophage/tumor-cell and therefore, in part, the host-tumour relationship, since otherwise an erroneous picture may be painted. strate
further
Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20014, U.S.A.
Viral Oncology Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda
STANISLAW M. MIKULSKI MICHAEL A. CHIRIGOS
SEPTIC SHOCK
SIR,-Although the article by Dr Ledingham and Mr McArdle’ contains a wealth of factual information, it makes little contribution to our understanding of the pathophysiology of the condition which could provide a base on which to plan treatment.
*
Reduction of mortality by early intermittent positive-pressure ventilation (i.P.P.v.) suggests that by squeezing a little more oxygen into the circulation and reducing consumption by the muscles of respiration, the effects of stagnant anoxia are reduced in severity and chances of survival thereby improved. The criteria by which the decision is taken to start I.P.P.V., are not, however, stated, except that it was started "early." Discussing the duration of shock Ledingham and McArdle say that, although the total duration of shock in their patients did not vary during the entire series, the duration before referral tended to increase "as appropriate treatment was initiated by the ward staff." I would have expected appropriate treatment to reduce duration and intensity. Did this treatment include massive dosage of antibiotics and did shock occur before or after the administration (release of endotoxin after wholesale destruction of gram-negative organisms can precipitate
shock)? Where does shock begin and where does it end? In the third of the series only two deaths were attributable to continuing shock yet five patients died from acute respiratory and renal failure. Albuminuria, hxmaturia, and reduced urine output are the earliest and most constant effects produced by bacterial toxins in laboratory animals.2 The kidney is the first organ affected so persistence of renal disorder indicates continuation of shock, although peripheral circulatory signs may have receded. The suggestion that pharmacological agents such as glucocorticoids could have an "action on the later stages of septic shock not hitherto described" is strange considering the volume of work devoted to this subject and the fact that glucocorticoids have maximum protective action in animals when given before endotoxin.3 Chlorpromazine also possesses similar maximum protective action before exposure to endotoxin,4 almost certainly through its deafferenting action on the brainstem reticular formation.55
13 1. 2.
Folkman, J., Ann. Surg., 1972, 175, 409. Ledingham, I. M., McArdle, C. S. Lancet, 1978, i, 1194.
Reilly, J., Compagnon, A., Laporte, A., Du Buit, H. Le Role du Système nerveux vegetatif en pathologie renale. Paris, 1942. 3. Lillenei, R. C., Longerbeam, J. N., Bloch, J. H., Manax, W. Clin. Pharmacol. Ther. 1964, 5, 63. 4. Reilly, J., Compagnon, A., Tournier, P., Du Buit, H. Ann. de Méd. 1954, 55, T5. 5. Bradley, P. B. in Reticular formation of the brain. Henry Ford symposium (edited by H. H. Jasper and others); p. 123. London, 1960. 6. Buxton Hopkin, D. A. Proc. Wld Congr. Anæsthesiol. 1977, p. 368.
SIR,-Professor Salmon and
.
and antigen-triggered B-lymphocyte proliferation. Monocyte-macrophage cells are the predominant source of colony-stimulating factor (c.s.F.) in myelopoiesis, and the same cells, at certain critical c.s.F. concentration, begin production of prostaglandin E which suppresses myelopoiesis.4 Feedback control of excessive myelopoiesis thus operates through the same growth-promoting and growth-inhibiting population of macrophage-like cells. Although the glycoprotein described by Salmon and Hamburger was antigenically dissimilar from the myelopoiesis-stimulating C.S.F., the point is that the same population of cells can demonstrate two diametrically opposite functions, dependent on quantitative differences of c.s.F. concentration. The suppression of B-cell-derived polyclonal humoral antibody production by monocyte-like cells has been shown by Broder et al. in some patients with myeloma. Whether the same cells are capable of stimulating monoclonal B cells in patients with myeloma remains to be established in vivo. The demonstration in vitro that macrophage-derived glycoprotein is also able to stimulate colony-formation of various other neoplastic cells is very intriguing. However, there is abundant evidence from laboratory animal and human systems that macrophage content of the tumour correlates with prognosis and risk of metastatic spread.6-9 Macrophages, although having limited capacity,’O protect to a certain extent against the tumour
spread 6- 10 and, they can selectively kill neoplastic but not normal cells.’Whether the presence of significant numbers of macrophages in malignant effusions represents a cause of rather than a protective response against, tumour growth will have to be established in vivo. Macrophages can produce several other humoral factors which are selectively tumoricidal and definitely do not promote tumour growth.llll2 Although very provocative, the suggestions that macrophages or macrophage-derived humoral factor(s) can promote the monoclonal neoplastic growth and that organ macrophage content can positively correlate with the promotion of tumour growth do contradict well-founded evidence of a protective role of macrophages against neoplastic growth and spread. The potentially beneficial role of macrophages in tumour-growth control has been ignored by Salmon and Hamburger, perhaps for the sake of clear and simplified presentation. It could be that the growth-stimulatory effect of a macrophage-derived factor on a minority of clonogenic cells in vivo counteracts the otherwise inhibitory effect of other macrophage-related factors 1. 2. 3. 4.
Salmon, S. E., Hamburger, A. Lancet, 1978, i, 1289. Prehn, R. T., Lappé, M. A. Transplant. Rev. 1971, 7, 26. Fidler, I. J. Cancer Res. 1974, 34, 491. Kurland, J. I., Bockman, R. S., Broxmeyer, H. E., Moore, M. A. S. Science, 1978, 199, 552. 5. Broder, S, Humphrey, R., Durm, M., Blackman, M., Meade, B., Goldman, C., Strober, W., Waldmann, T. A. New Engl. J. Med., 1975, 293, 887. 6. Eccles, S. A., Alexander, P. Nature, 1974, 250, 667. 7. Evans, R., Alexander, P. ibid., 1972, 236, 168. 8. Schultz, R. M., Papamatheakis, J. D., Stylos, W. A., Chirigos, M. A. Cell. Immun. 1976, 25, 309. 9. Hibbs, J. B., Jr., Lambert, L. H., Jr., Remington, J. S. Nature neō Biol.,
1972, 235, 48. 10. Lancet, 1976, ii, 27. 11. Currie, G. A., Basham, C.J. exp. Med., 1975, 142, 1600. 12. Carswell, E. A., Old, L. J., Kassel, R. L., Green, S., Fiore, N., B. Proc nat. Acad Sci. U.S.A., 1975, 72, 3666.
Williamson,
This might limit the capacity of macroinhibit tumour growth. The possibility of imphages elimination of the clonogenic-promoting munologically specific factor(s) and exploration of its properties (e.g., does it demon-
on tumour
growth.
alone
to
angiogenesis-promoting characteristics?") warrant investigation. It is important, even when presenting a hypothesis, to try to encompass all important aspects of the macrophage/tumor-cell and therefore, in part, the host-tumour relationship, since otherwise an erroneous picture may be painted. strate
further
Cancer Therapy Evaluation Program, Division of Cancer Treatment, National Cancer Institute, Bethesda, Maryland 20014, U.S.A.
Viral Oncology Program, Division of Cancer Cause and Prevention, National Cancer Institute, Bethesda
STANISLAW M. MIKULSKI MICHAEL A. CHIRIGOS
SEPTIC SHOCK
SIR,-Although the article by Dr Ledingham and Mr McArdle’ contains a wealth of factual information, it makes little contribution to our understanding of the pathophysiology of the condition which could provide a base on which to plan treatment.
*
Reduction of mortality by early intermittent positive-pressure ventilation (i.P.P.v.) suggests that by squeezing a little more oxygen into the circulation and reducing consumption by the muscles of respiration, the effects of stagnant anoxia are reduced in severity and chances of survival thereby improved. The criteria by which the decision is taken to start I.P.P.V., are not, however, stated, except that it was started "early." Discussing the duration of shock Ledingham and McArdle say that, although the total duration of shock in their patients did not vary during the entire series, the duration before referral tended to increase "as appropriate treatment was initiated by the ward staff." I would have expected appropriate treatment to reduce duration and intensity. Did this treatment include massive dosage of antibiotics and did shock occur before or after the administration (release of endotoxin after wholesale destruction of gram-negative organisms can precipitate
shock)? Where does shock begin and where does it end? In the third of the series only two deaths were attributable to continuing shock yet five patients died from acute respiratory and renal failure. Albuminuria, hxmaturia, and reduced urine output are the earliest and most constant effects produced by bacterial toxins in laboratory animals.2 The kidney is the first organ affected so persistence of renal disorder indicates continuation of shock, although peripheral circulatory signs may have receded. The suggestion that pharmacological agents such as glucocorticoids could have an "action on the later stages of septic shock not hitherto described" is strange considering the volume of work devoted to this subject and the fact that glucocorticoids have maximum protective action in animals when given before endotoxin.3 Chlorpromazine also possesses similar maximum protective action before exposure to endotoxin,4 almost certainly through its deafferenting action on the brainstem reticular formation.55
13 1. 2.
Folkman, J., Ann. Surg., 1972, 175, 409. Ledingham, I. M., McArdle, C. S. Lancet, 1978, i, 1194.
Reilly, J., Compagnon, A., Laporte, A., Du Buit, H. Le Role du Système nerveux vegetatif en pathologie renale. Paris, 1942. 3. Lillenei, R. C., Longerbeam, J. N., Bloch, J. H., Manax, W. Clin. Pharmacol. Ther. 1964, 5, 63. 4. Reilly, J., Compagnon, A., Tournier, P., Du Buit, H. Ann. de Méd. 1954, 55, T5. 5. Bradley, P. B. in Reticular formation of the brain. Henry Ford symposium (edited by H. H. Jasper and others); p. 123. London, 1960. 6. Buxton Hopkin, D. A. Proc. Wld Congr. Anæsthesiol. 1977, p. 368.
