- Email: [email protected]
Mast cell density, angiogenesis, and their significance in tumor development
628
Letters to the Editor
in a postmenopausal patient with an intrauterine contraceptive device in place for over 20 years. Gynecol Oncol 1998 (Mar);68(3):288 – 92. [11] Zucca E, Conconi A. Treatment of Extr anodal lymphoma. Best Pract Res, Clin Haematol 2002 (Sep);15(3):533 – 47. [12] Smith DF, Klopp CT. The value of surgical removal of localized lymphomas: II. Evaluation of roentgen ray therapy. Am Surg 1961;27:755 – 8. [13] Mann R, Roberts WS, Gunasakeran S, Tralins A. Primary lymphoma of the uterine cervix. Gynecol Oncol 1987 (Jan);26(1):127 – 34.
Polat Dursun4 Murat Gultekin Ali Ayhan Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey E-mail address: [email protected]. 4 Corresponding author. Fax: +90 312 3116372. 4 November 2005 doi:10.1016/j.ygyno.2005.11.011
Mast cell density, angiogenesis, and their significance in tumor development To the Editor: I read the article by Chan et al. describing dMast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancerT with great interest [1]. My interest in this study is that we demonstrated in vitro human Mast cell (MC)-mediated cytotoxicity against different human leukemia/ lymphoma tumors, supporting their study conclusion of MC infiltration predicting for improved survival [2,3]. And I also have some comments about quite controversial MC-induced tumor angiogenesis and anti-tumor effects of MC in light of very recent literature and our findings. This study demonstrated that peritumoral MC infiltration predicts improved survival in advanced ovarian cancer [1]. Consistent with this study, increased MC density (MCD) has not been always found to be associated with bad prognosis/ increased metastasis; it can also indicate a good prognosis/better survival, such as in soft tissue sarcomas, breast, stomach and colorectal cancers. Studies have shown that MC-deficient mice had an increased tumor incidence compared to normal. This increased tumor incidence was suppressed to the normal level when MC deficiency had been overcome. In addition, tumor incidence and growth were inversely correlated with MC numbers in the tissues of MC-deficient, partially MC-depleted, and MC-sufficient mice. In some studies, there was no significant correlation between MCD and the stage of the tumor, such as in human hepatocellular, nonsmall cell lung and some breast cancers as well as melanoma, lymphoplasmocytic lymphoma and chronic lymphoid leukemia. Although it is hard to explain these conflicting results, they may be due to wide variations in timing, tumor type as well as methodologies used for the demonstration of MC, inflammatory cells and vessels. MCs are multifunctional cells and have recently shown that they can also act as effector elements of the human immune
system. Although some still postulate MCs to be enhancers of tumor development, especially through their effects on angiogenesis; mounting evidence also indicates that MCs could inhibit tumor growth. As described in this study [1], dhigher MC numbers are associated with more indolent tumor growthT, suggesting the possibility of tumor inhibitory effects of MCs. Currently, believers in the inhibitory role of MCs assume them as inhibitors of tumor development through their pro-necrolytic/-apoptotic granules e.g. TNF-alpha and granzymes. The first observations of their possible role as antitumor cells in peri/intratumoral tissue were mentioned five decades ago. It was believed that murine MC has natural cytotoxicity against sensitive murine cell lines (WEHI-164 and L929) by different mechanisms, either dependent on TNFalpha or not. Later studies suggest that MC can kill targets through degranulation of proteases, leukotrienes and NO. MCs, like cytotoxic-killer cells, were also demonstrated to contain abundant serine proteases termed granzymes including several chymases in their granules, which is implicated in cellmediated cytotoxicity. Recently, cultured MCs have also been proven to contain granzyme B and express Fas Ligand. MC chymase was demonstrated to induce apoptosis in neonatal rat cardiomyocytes and human vascular smooth muscle cells [4]. Experimental studies have shown that chymase induces the accumulation of tumor associated macrophages, neutrophils and other inflammatory cells in vivo suggesting contribution to MC cytotoxicity indirectly. Our in vitro studies suggested that increased chymase content of MCs in long-term culture could have played a role to mediate MC cytotoxicity (unpublished observation). Thus, MC cytotoxicity seems to be mediated by at least 2 pathways: by secretory pathways via exocytosis of granules containing serine proteases such as granzymes, chymase and soluble TNF-alpha and nonsecretory (cell-to-cell contact) pathways via membranous TNF-alpha and FasL. We are the first to show in vitro human MC cytotoxicity against NK/LAK-sensitive/resistant human leukemia/lymphoma cells [2,3]. This study showed that peritumoral MC infiltration with high microvessel density could be a marker of predicting for improved survival in advanced ovarian cancer. Consistent with this study, high microvessel density and MCD in some tumors e.g. oral squamous carcinoma were also found to be associated with a greater probability of survival. This study did find no significant association between angiogenesis and MCD, indicating some other cells and/or factors contributing angiogenesis. Interestingly, in some mice studies, no significant difference between MCdeficient and sufficient ones was found for the angiogenesis consistent with this study. In vitro MC-mediated apoptosis of endothelial cells was also shown. Some hold macrophage infiltration, fibroblasts and/or the tumor itself responsible for human neoplastic angiogenesis. Essentially, heparin-like molecules, IL-8 and tryptase were believed was responsible for neovascularization. There could also be other mediators released from MC and/or tumor in the stroma inducing angiogenesis e.g. chymase, SCF, b-FGF, TGF-beta and histamine. Although some researchers currently hold angiopoietins responsible for the angiogenesis, the prognostic role of angiogenesis in tumor
Letters to the Editor
development is still not certain. Many hold angiopoietin-2 responsible for progression of brain, ovarian, hepatocellular and bladder cancers. In addition to the authors’ speculation about recruiting of fibroblasts leading to tumor fibrosis and limiting cancer growth by tryptase, it is actually blamed for the in vivo angiogenesis [5]. Thus, both fibrosis and angiogenesis mediated by MC tryptase may contribute the overall better survival in an advanced ovarian cancer. Is the MC really an active player or an innocent passerby? The point is that increased MCD could be primary and/or secondary since MC numbers are also found to be increased physiologically around healing tissue, scars and ovulation. MCs might also just be a reflection of a generalized inflammatory reaction of the immune system. Moreover, some researchers think that the MCs may represent reactive cell types involved in the pathophysiology of the host reaction, e.g. in breast cancer and early gastric cancer. Consequently, some angiogenic factors in this tumor-induced inflammatory reaction may stimulate MC migration. As a result, observing increased MCD in only tumor tissue with bad/good prognosis on pathological specimens seems to be insufficient to explain the real role of MC in that tissue. Additional in vitro and in vivo studies are needed to further clarify the role of MCs in relation to tumor cells. In conclusion, I agree that MC infiltration as an additional pathologic parameter can be used to show a better survival rate supported by our in vitro studies. I also personally believe that the inhibitory or proliferative effect of MCs on tumor development depends on multiple interactions among MC type, tumor type and the environment. References [1] Chan JK, Magistris A, Loizzi V, Lin F, Rutgers J, Osann K, et al. Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 2005;99:20 – 5. ¨ zdemir O ¨ , Moore C, Ravindranath Y, Savasan S. Can mast cells mediate [2] O natural cytotoxicity in short term culture? Ann Allergy Asthma Immunol 94 (1) (2004) 185, P216 [abstract]. ¨ zdemir O ¨ . Immunosurveillance function of human mast cell? World J. [3] O Gastroenterol [in press]. [4] Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT. Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 2003;23:238 – 43. [5] Benitez-Bribiesca L, Wong A, Utrera D, Castellanos E. The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem 2001;49:1061 – 2.
¨ ner O ¨ zdemir O Department of Pediatrics, Division of Allergy/Immunology, 1542 Tulane Avn., T8-1, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA E-mail address: [email protected]. Fax: +1 504 568 7598. 10 September 2005 doi:10.1016/j.ygyno.2005.11.024
629
The importance of vascular immune regulation in the prognosis of women with advanced ovarian cancer To the editor: ¨ zdemir’s comments [1] regarding our We concur with Dr. O research findings [2]. The recent increase in the amount of literature on mast cell function in various cancers is intriguing. Since the submission of our manuscript, there have been several reports on the prognostic value of mast cells with interesting results. For example, Welch et al. showed that the presence of tumor islet mast cells and increasing islet/stromal mast-cell ratio were favorable independent prognostic indicators in non-small-cell lung cancer [3]. On the other hand, Kojima et al. showed that mast cell density and microvessel density were significant prognostic factors for poorer survival in lung adenocarcinoma [4]. However, given the close association between mast cell density and tumor-cell VEGF, these authors were not able confirm the findings on multivariate analysis. Recently, our lab has demonstrated that mast cell granules contain numerous biologically active compounds such as histamine, tryptase, heparin, and chymase [5]. Some of these mast cell compounds and metabolites are likely to have significant effects on fibroblasts and endothelial cells that remain to be defined. In addition, a number of other mediators from fibroblasts and mast cells could potentially influence tumor growth through a variety of mechanisms such as cyclooxygenase metabolites and heparanases. The net effect of mast cells on tumor growth, therefore, is likely to be the result of multiple interactions between the various components of mast cell granules and adjacent stromal cells such as vascular endothelium and fibroblasts. In summary, we believe that the interaction between mast cells, fibrosis, and angiogenesis is complex. With an improvement in the techniques of evaluating mast cells, angiogenesis and associated inflammatory cells and their signaling pathways, the immune-modulatory function of the mast cell will be further elucidated. References ¨ zdemir O ¨ . Mast cell density, angiogenesis, and their significance in tumor [1] O development. Gynecol Oncol 2006;100:628 – 9. [2] Chan JK, Magistris A, Loizzi V, et al. Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 2005;99:20 – 5. [3] Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 2005;23:1 – 9. [4] Kojima H, Shijubo N, Yamada G, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 2005; 104:1668 – 77. [5] Samoszuk M, Kanakubo E, Chan JK. Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts. BMC Cancer 2005;5:121.
Letters to the Editor
in a postmenopausal patient with an intrauterine contraceptive device in place for over 20 years. Gynecol Oncol 1998 (Mar);68(3):288 – 92. [11] Zucca E, Conconi A. Treatment of Extr anodal lymphoma. Best Pract Res, Clin Haematol 2002 (Sep);15(3):533 – 47. [12] Smith DF, Klopp CT. The value of surgical removal of localized lymphomas: II. Evaluation of roentgen ray therapy. Am Surg 1961;27:755 – 8. [13] Mann R, Roberts WS, Gunasakeran S, Tralins A. Primary lymphoma of the uterine cervix. Gynecol Oncol 1987 (Jan);26(1):127 – 34.
Polat Dursun4 Murat Gultekin Ali Ayhan Department of Obstetrics and Gynecology, Faculty of Medicine, Hacettepe University, Ankara, Turkey E-mail address: [email protected]. 4 Corresponding author. Fax: +90 312 3116372. 4 November 2005 doi:10.1016/j.ygyno.2005.11.011
Mast cell density, angiogenesis, and their significance in tumor development To the Editor: I read the article by Chan et al. describing dMast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancerT with great interest [1]. My interest in this study is that we demonstrated in vitro human Mast cell (MC)-mediated cytotoxicity against different human leukemia/ lymphoma tumors, supporting their study conclusion of MC infiltration predicting for improved survival [2,3]. And I also have some comments about quite controversial MC-induced tumor angiogenesis and anti-tumor effects of MC in light of very recent literature and our findings. This study demonstrated that peritumoral MC infiltration predicts improved survival in advanced ovarian cancer [1]. Consistent with this study, increased MC density (MCD) has not been always found to be associated with bad prognosis/ increased metastasis; it can also indicate a good prognosis/better survival, such as in soft tissue sarcomas, breast, stomach and colorectal cancers. Studies have shown that MC-deficient mice had an increased tumor incidence compared to normal. This increased tumor incidence was suppressed to the normal level when MC deficiency had been overcome. In addition, tumor incidence and growth were inversely correlated with MC numbers in the tissues of MC-deficient, partially MC-depleted, and MC-sufficient mice. In some studies, there was no significant correlation between MCD and the stage of the tumor, such as in human hepatocellular, nonsmall cell lung and some breast cancers as well as melanoma, lymphoplasmocytic lymphoma and chronic lymphoid leukemia. Although it is hard to explain these conflicting results, they may be due to wide variations in timing, tumor type as well as methodologies used for the demonstration of MC, inflammatory cells and vessels. MCs are multifunctional cells and have recently shown that they can also act as effector elements of the human immune
system. Although some still postulate MCs to be enhancers of tumor development, especially through their effects on angiogenesis; mounting evidence also indicates that MCs could inhibit tumor growth. As described in this study [1], dhigher MC numbers are associated with more indolent tumor growthT, suggesting the possibility of tumor inhibitory effects of MCs. Currently, believers in the inhibitory role of MCs assume them as inhibitors of tumor development through their pro-necrolytic/-apoptotic granules e.g. TNF-alpha and granzymes. The first observations of their possible role as antitumor cells in peri/intratumoral tissue were mentioned five decades ago. It was believed that murine MC has natural cytotoxicity against sensitive murine cell lines (WEHI-164 and L929) by different mechanisms, either dependent on TNFalpha or not. Later studies suggest that MC can kill targets through degranulation of proteases, leukotrienes and NO. MCs, like cytotoxic-killer cells, were also demonstrated to contain abundant serine proteases termed granzymes including several chymases in their granules, which is implicated in cellmediated cytotoxicity. Recently, cultured MCs have also been proven to contain granzyme B and express Fas Ligand. MC chymase was demonstrated to induce apoptosis in neonatal rat cardiomyocytes and human vascular smooth muscle cells [4]. Experimental studies have shown that chymase induces the accumulation of tumor associated macrophages, neutrophils and other inflammatory cells in vivo suggesting contribution to MC cytotoxicity indirectly. Our in vitro studies suggested that increased chymase content of MCs in long-term culture could have played a role to mediate MC cytotoxicity (unpublished observation). Thus, MC cytotoxicity seems to be mediated by at least 2 pathways: by secretory pathways via exocytosis of granules containing serine proteases such as granzymes, chymase and soluble TNF-alpha and nonsecretory (cell-to-cell contact) pathways via membranous TNF-alpha and FasL. We are the first to show in vitro human MC cytotoxicity against NK/LAK-sensitive/resistant human leukemia/lymphoma cells [2,3]. This study showed that peritumoral MC infiltration with high microvessel density could be a marker of predicting for improved survival in advanced ovarian cancer. Consistent with this study, high microvessel density and MCD in some tumors e.g. oral squamous carcinoma were also found to be associated with a greater probability of survival. This study did find no significant association between angiogenesis and MCD, indicating some other cells and/or factors contributing angiogenesis. Interestingly, in some mice studies, no significant difference between MCdeficient and sufficient ones was found for the angiogenesis consistent with this study. In vitro MC-mediated apoptosis of endothelial cells was also shown. Some hold macrophage infiltration, fibroblasts and/or the tumor itself responsible for human neoplastic angiogenesis. Essentially, heparin-like molecules, IL-8 and tryptase were believed was responsible for neovascularization. There could also be other mediators released from MC and/or tumor in the stroma inducing angiogenesis e.g. chymase, SCF, b-FGF, TGF-beta and histamine. Although some researchers currently hold angiopoietins responsible for the angiogenesis, the prognostic role of angiogenesis in tumor
Letters to the Editor
development is still not certain. Many hold angiopoietin-2 responsible for progression of brain, ovarian, hepatocellular and bladder cancers. In addition to the authors’ speculation about recruiting of fibroblasts leading to tumor fibrosis and limiting cancer growth by tryptase, it is actually blamed for the in vivo angiogenesis [5]. Thus, both fibrosis and angiogenesis mediated by MC tryptase may contribute the overall better survival in an advanced ovarian cancer. Is the MC really an active player or an innocent passerby? The point is that increased MCD could be primary and/or secondary since MC numbers are also found to be increased physiologically around healing tissue, scars and ovulation. MCs might also just be a reflection of a generalized inflammatory reaction of the immune system. Moreover, some researchers think that the MCs may represent reactive cell types involved in the pathophysiology of the host reaction, e.g. in breast cancer and early gastric cancer. Consequently, some angiogenic factors in this tumor-induced inflammatory reaction may stimulate MC migration. As a result, observing increased MCD in only tumor tissue with bad/good prognosis on pathological specimens seems to be insufficient to explain the real role of MC in that tissue. Additional in vitro and in vivo studies are needed to further clarify the role of MCs in relation to tumor cells. In conclusion, I agree that MC infiltration as an additional pathologic parameter can be used to show a better survival rate supported by our in vitro studies. I also personally believe that the inhibitory or proliferative effect of MCs on tumor development depends on multiple interactions among MC type, tumor type and the environment. References [1] Chan JK, Magistris A, Loizzi V, Lin F, Rutgers J, Osann K, et al. Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 2005;99:20 – 5. ¨ zdemir O ¨ , Moore C, Ravindranath Y, Savasan S. Can mast cells mediate [2] O natural cytotoxicity in short term culture? Ann Allergy Asthma Immunol 94 (1) (2004) 185, P216 [abstract]. ¨ zdemir O ¨ . Immunosurveillance function of human mast cell? World J. [3] O Gastroenterol [in press]. [4] Leskinen MJ, Lindstedt KA, Wang Y, Kovanen PT. Mast cell chymase induces smooth muscle cell apoptosis by a mechanism involving fibronectin degradation and disruption of focal adhesions. Arterioscler Thromb Vasc Biol 2003;23:238 – 43. [5] Benitez-Bribiesca L, Wong A, Utrera D, Castellanos E. The role of mast cell tryptase in neoangiogenesis of premalignant and malignant lesions of the uterine cervix. J Histochem Cytochem 2001;49:1061 – 2.
¨ ner O ¨ zdemir O Department of Pediatrics, Division of Allergy/Immunology, 1542 Tulane Avn., T8-1, Louisiana State University Health Sciences Center, New Orleans, LA 70112, USA E-mail address: [email protected]. Fax: +1 504 568 7598. 10 September 2005 doi:10.1016/j.ygyno.2005.11.024
629
The importance of vascular immune regulation in the prognosis of women with advanced ovarian cancer To the editor: ¨ zdemir’s comments [1] regarding our We concur with Dr. O research findings [2]. The recent increase in the amount of literature on mast cell function in various cancers is intriguing. Since the submission of our manuscript, there have been several reports on the prognostic value of mast cells with interesting results. For example, Welch et al. showed that the presence of tumor islet mast cells and increasing islet/stromal mast-cell ratio were favorable independent prognostic indicators in non-small-cell lung cancer [3]. On the other hand, Kojima et al. showed that mast cell density and microvessel density were significant prognostic factors for poorer survival in lung adenocarcinoma [4]. However, given the close association between mast cell density and tumor-cell VEGF, these authors were not able confirm the findings on multivariate analysis. Recently, our lab has demonstrated that mast cell granules contain numerous biologically active compounds such as histamine, tryptase, heparin, and chymase [5]. Some of these mast cell compounds and metabolites are likely to have significant effects on fibroblasts and endothelial cells that remain to be defined. In addition, a number of other mediators from fibroblasts and mast cells could potentially influence tumor growth through a variety of mechanisms such as cyclooxygenase metabolites and heparanases. The net effect of mast cells on tumor growth, therefore, is likely to be the result of multiple interactions between the various components of mast cell granules and adjacent stromal cells such as vascular endothelium and fibroblasts. In summary, we believe that the interaction between mast cells, fibrosis, and angiogenesis is complex. With an improvement in the techniques of evaluating mast cells, angiogenesis and associated inflammatory cells and their signaling pathways, the immune-modulatory function of the mast cell will be further elucidated. References ¨ zdemir O ¨ . Mast cell density, angiogenesis, and their significance in tumor [1] O development. Gynecol Oncol 2006;100:628 – 9. [2] Chan JK, Magistris A, Loizzi V, et al. Mast cell density, angiogenesis, blood clotting, and prognosis in women with advanced ovarian cancer. Gynecol Oncol 2005;99:20 – 5. [3] Welsh TJ, Green RH, Richardson D, Waller DA, O’Byrne KJ, Bradding P. Macrophage and mast-cell invasion of tumor cell islets confers a marked survival advantage in non-small-cell lung cancer. J Clin Oncol 2005;23:1 – 9. [4] Kojima H, Shijubo N, Yamada G, et al. Clinical significance of vascular endothelial growth factor-C and vascular endothelial growth factor receptor 3 in patients with T1 lung adenocarcinoma. Cancer 2005; 104:1668 – 77. [5] Samoszuk M, Kanakubo E, Chan JK. Degranulating mast cells in fibrotic regions of human tumors and evidence that mast cell heparin interferes with the growth of tumor cells through a mechanism involving fibroblasts. BMC Cancer 2005;5:121.