Clinical significance of macrophage heterogeneity in human malignant tumors with articles on down-regulating VEGF

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It has long been known that many leukocytes including macrophages are present in tumor tissues and that these cells, together with fibroblasts and vascular endothelial cells, form the tumor microenvironment.[1-4] Previously, activated macrophages were believed to exhibit antitumor activity by directly attacking tumor cells in the tumor microenvironment.[5] However, many recent studies have indicated the protumoral functions of tumor-associated macrophages (TAMs), and thus, TAMs are believed to directly or indirectly promote tumor progression.[6-8] Great advances have been made in TAM research over the past dozen years or so, with one of the most significant breakthroughs being the development of immunohistochemical methods for identifying TAMs in tumor tissue. Numerous studies using human samples have been carried out using CD68 as a macrophage marker, whereas CD163 and CD204 have been used as markers of M2 macrophages in recent studies.[9, 10] Although variability is observed according to tumor tissue type and location, over 80% of immunohistochemical studies using various human tumor tissues have shown that higher numbers of TAMs are associated with worse clinical prognosis.[9] Supporting these clinical observations, in vitro experiments using human tumor cells and experiments using animal models indicate that TAMs promote tumor cell growth by suppressing antitumor immunity and inducing angiogenesis.[11, 12]


TAMs promote tumor progression through induction of angiogenesis and suppression of antitumor immunity. In particular, in humans, protumoral TAMs are believed to exhibit characteristics similar to M2 macrophages, and are intimately involved in the progression of malignant tumors. As such, treatment strategies aimed at local inhibition of macrophage differentiation into the M2 phenotype are anticipated to be effective. Signal transduction pathways, including nuclear factor (NF)-?B, Stat3, Stat6, c-Myc, and interferon regulatory factor 4, are involved in differentiation into the M2 phenotype.[13, 14-16] Nuclear factor-?B and Stat3 are also strongly involved in tumor cell growth, and drugs targeting these molecules are currently being developed. Among such molecule-specific drugs, synergistic efficacy due to direct effects on tumor cells, as well as inhibition of the differentiation of TAMs into the M2 phenotype, is expected. Among drugs currently in use, some are active against TAMs. Cyclosporin A and trabectedin not only directly inhibit tumor cell growth, they also suppress activation of TAMs.[17] Bisphosphonates not only suppress bone resorption by osteoclasts, they also inhibit the differentiation of TAMs into the M2 phenotype. The angiogenic inhibitor bevacizumab (a VEGF-inhibiting antibody) has recently been used to treat solid tumors such as colorectal adenocarcinoma, and this drug also exhibits antitumor activity by suppressing TAM migration.[18]



Komohara Y et al. Cancer Science. Volume 105, Issue 1, pages 1–8, January 2014. DOI: 10.1111/cas.12314



1. Monis B, Weinberg T. Cytochemical study of esterase activity of human neoplasms and stromal macrophages. Cancer 1961; 14: 369–77.

2. Underwood JC, Carr I. The ultrastructure of the lymphoreticular cells in non-lymphoid human neoplasms. Virchows Arch B Cell Pathol 1972; 12: 39–50.

3. Lauder I, Aherne W, Stewart J, Sainsbury R. Macrophage infiltration of breast tumours: a prospective study. J Clin Pathol 1977; 30: 563–8.

4. Kreutz M, Fritsche J, Andreesen R. Macrophages in tumor biology. In; Burke B, Lewis CE, eds. The Macrophage, 2nd edn. Oxford, UK: Oxford Univ. Press, 2002; 458–89.

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6. Mantovani A, Sozzani S, Locati M, Allavena P, Sica A. Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends Immunol 2002; 23: 549–55.

7. Bingle L, Brown NJ, Lewis CE. The role of tumour-associated macrophages in tumour progression: implications for new anticancer therapies. J Pathol 2002; 196: 254–65.

8. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 2004; 4: 71–8.

9. Heusinkveld M, van der Burg SH. Identification and manipulation of tumor associated macrophages in human cancers. J Transl Med 2011; 9: 216.

10. Komohara Y, Ohnishi K, Kuratsu J, Takeya M. Possible involvement of the M2 anti-inflammatory macrophage phenotype in growth of human gliomas. J Pathol 2008; 216: 15–24.

11. Sica A, Schioppa T, Mantovani A, Allavena P. Tumour-associated macrophages are a distinct M2 polarised population promoting tumour progression: potential targets of anti-cancer therapy. Eur J Cancer 2006; 42: 717–27.

12. Yu H, Kortylewski M, Pardoll D. Crosstalk between cancer and immune cells: role of STAT3 in the tumour microenvironment. Nat Rev Immunol 2007; 7: 41–51.

13. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Invest 2012; 122: 787–95.

14. Pello OM, De Pizzol M, Mirolo M et al. Role of c-MYC in alternative activation of human macrophages and tumor-associated macrophage biology. Blood 2012; 119: 411–21.

15. Satoh T, Takeuchi O, Vandenbon A et al. The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nat Immunol 2010; 11: 936–44.

16. Lawrence T, Natoli G. Transcriptional regulation of macrophage polarization: enabling diversity with identity. Nat Rev Immunol 2011; 11: 750–61.

17. Germano G, Frapolli R, Belgiovine C et al. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell 2013; 23: 249–62.

18. Roland CL, Dineen SP, Lynn KD et al. Inhibition of vascular endothelial growth factor reduces angiogenesis and modulates immune cell infiltration of orthotopic breast cancer xenografts. Mol Cancer Ther 2009; 8: 1761–71.



Vascular abnormalities inside tumors are important factors resulting in abnormal tumor microenvironment. Microenvironment was closely correlated with the malignant degrees, metastasis, and recurrence of tumors. Besides, the acid environment, oxygen deficiency, and other factors it induced may severely affect the efficacies of routine therapies, radiotherapy and chemotherapy. Anti-angiogenesis treatment drugs targeting vascular endothelial growth factor (VEGF) not only antagonize the angiogenesis of tumor vessels, but also promote the vascular normalization inside tumors to some extent, thus reducing interstitial hypertension, improving blood flow inside tumors, and enhancing therapeutic efficacies. Previous clinical and experimental studies have proved that many Chinese herbs show enhancing effects of chemotherapy and radiotherapy in comprehensive treatment of chemotherapy and radiotherapy combination. Meanwhile, recent studies have also proved that many Chinese herbs could fight against tumor vascular angiogenesis, lower serum VEGF concentration, and inhibit expressions of VEGF. Therefore, studying Chinese herbs’ mechanisms of anti-tumor from promoting vascular normalization will open up a brand new field for seeking a cut-in point for Chinese medicine therapy in the comprehensive treatment, optimizing a treatment protocols, and further clarifying the roles of Chinese medicine in the comprehensive treatment.Source


You J. Study on the tumor microenvironment and tumor vascular normalization in integrative treatment of tumor by Chinese medicine and western medicine. Zhongguo Zhong Xi Yi Jie He Za Zhi. 2011 Aug;31(8):1127-31.

Medicinal herbs and their phytochemicals are potential novel leads for developing antiangiogenic drugs. This review aims to assess the current status of research with medicinal herbs and their phytochemicals for the development of antiangiogenic agents for cancer and other angiogenesis-related diseases including inflammation, diabetic retinopathy, endometriosis and obesity. Most studies reviewed have focused on vascular endothelial growth factor (VEGF)/vascular endothelial growth factor receptor 2 (VEGFR-2) signaling for endothelial response processes and have led to the identification of many potential antiangiogenic agents. Since human clinical trials with antiangiogenic modalities targeting VEGF/VEGFR-2 signaling have shown limited efficacy and occasional toxic side effects, screening strategies for herbal phytochemicals based on other signaling pathways important for cancer-endothelial and stromal crosstalks should be emphasized in the future.


Jeong SJ, Koh W, Lee EO, Lee HJ, Lee HJ, Bae H, Lü J, Kim SH. Antiangiogenic phytochemicals and medicinal herbs. Phytother Res. 2011 Jan;25(1):1-10. doi: 10.1002/ptr.3224. DOI: 10.1002/ptr.3224

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