研究發現腫瘤微環境中腫瘤巨噬細胞是主要的細胞族群並且是以 M2 型態的巨噬細胞存在。然而到目前為止哪些機制參與了腫瘤巨噬細胞的分化仍然並不是很清楚。先前實驗室研究發現，腫瘤微環境中，肝癌細胞分泌未知內源性的配體，能夠促進 TLR2 的訊息傳遞幫助 ERK1/2 的磷酸化與自噬作用的產生促進 NF-κB p65 的降解，進而使得巨噬細胞分化成 M2 的型態。然而在先前的研究中， TLR2的訊息傳遞是經由哪些機制調控 ERK1/2 的磷酸化作用與引起自噬作用並不清楚，需進一步的證實。在我們的研究初步發現了，當巨噬細胞與肝腫瘤細胞培養液共同培養時，促進細胞產生活性氧化物質，並且這些活性氧化物質的產生使得 ERK1/2 的磷酸化作用與自噬作用促進 NF-κBp65 降解，進而促進巨噬細胞分化成 M2 的型態。此外也進一步在第二型的 NADPH 氧化酶 (NOX2) 缺陷細胞發現，活性氧化物質誘導的 NF-κBp65 降解的效果會減少，而且也發現 TLR2參與了 NOX2 調控的 M2 型態巨噬細胞分化。在另一方面，我們也發現肝癌細胞可以分泌 HMGB1 ，且 HMGB1 已經被了解是一種內源性 TLR2 的受體。初步的實驗藉由兩種方式減少肝腫瘤細胞培養液中的 HMGB1，包含利用shRNA減少細胞HMGB1 基因表現或中和性抗體的方式，實驗結果發現顯著的減少巨噬細胞中的活性氧化物質生成、 ERK1/2 磷酸化、自噬作用引起的NF-κBp65降解與巨噬細胞M2型態的分化。此外也發現可溶性的 HMGB1 透過TLR2 的訊息傳遞誘導自噬作用引起的 NF-κB p65 降解與巨噬細胞 M2 型態的分化。最後在原位的肝癌動物模型，我們發現 HMGB1 能夠調節腫瘤的形成和吸引 M2 型態巨噬細胞。從這些結果發現了 HMGB1 調控 TLR2/ NOX2 訊息產生活性氧化物質，進而誘發 M2 型態的巨噬細胞分化。

Tumor-associated macrophages (TAM) are considered to be a major cell population in the tumor microenvironment and can be differentiated into M2 phenotype supporting tumor existence. However, the switching mechanisms of polarized TAM by tumor cells are yet to be determined. We previously showed that unknown factors in the hepatoma microenvironment trigger Toll like receptor 2 (TLR2) signaling to induce the degradation of NF-κB p65 via ERK1/2 activation and autophagy promoting the polarization of M2 macrophages. The underlying mechanism is yet to be determined. In this study we found hepatoma conditioned medium stimulates reactive oxygen species (ROS) to trigger ERK1/2 activation, autophagy-mediated NF-κB degradation and M2 macrophage polarization. This ROS-mediated NF-κB p65 degradation was attenuated in NADPH oxidase 2 (NOX2)-deficient cells. In addition, TLR2 signaling was found to be involved in NOX2-regulated M2 macrophage polarization. An endogenous TLR2 ligand, high-mobility group protein B1 (HMGB1), was found to be secreted by hepatoma cells. HMGB1 suppression by RNA-silencing or neutralizing antibody reduces ROS generation, ERK1/2 activation, autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization. Our findings suggest that soluble HMGB1 can trigger TLR2 -dependent autophagy-mediated NF-κB p65 degradation and M2 macrophage polarization. Furthermore, we demonstrated that HMGB1 regulates tumor nodule formation and M2 macrophage recruitment in an in situ mice hepatoma model. In conclusion, we found a novel function of HMGB1 to regulate-TLR2/NOX2 dependent M2 polarization and TAM recruitment in hepatoma.

Baghdadi, M., Yoneda, A., Yamashina, T., Nagao, H., Komohara, Y., Nagai, S., Akiba, H., Foretz, M., Yoshiyama, H., Kinoshita, I., et al. (2013). TIM-4 glycoprotein-mediated degradation of dying tumor cells by autophagy leads to reduced antigen presentation and increased immune tolerance. Immunity 39, 1070-1081.
Bald, T., Quast, T., Landsberg, J., Rogava, M., Glodde, N., Lopez-Ramos, D., Kohlmeyer, J., Riesenberg, S., van den Boorn-Konijnenberg, D., Homig-Holzel, C., et al. (2014). Ultraviolet-radiation-induced inflammation promotes angiotropism and metastasis in melanoma. Nature 507, 109-113.
Bedard, K., and Krause, K.H. (2007). The NOX family of ROS-generating NADPH oxidases: physiology and pathophysiology. Physiological reviews 87, 245-313.
Benn, J., and Schneider, R.J. (1994). Hepatitis B virus HBx protein activates Ras-GTP complex formation and establishes a Ras, Raf, MAP kinase signaling cascade. Proc Natl Acad Sci U S A 91, 10350-10354.
Biswas, S.K., and Lewis, C.E. (2010). NF-kappaB as a central regulator of macrophage function in tumors. J Leukoc Biol 88, 877-884.
Blanchetot, C., and Boonstra, J. (2008). The ROS-NOX connection in cancer and angiogenesis. Crit Rev Eukaryot Gene Expr 18, 35-45.
Bonaldi, T., Talamo, F., Scaffidi, P., Ferrera, D., Porto, A., Bachi, A., Rubartelli, A., Agresti, A., and Bianchi, M.E. (2003). Monocytic cells hyperacetylate chromatin protein HMGB1 to redirect it towards secretion. EMBO J 22, 5551-5560.
Bosch, F.X., Ribes, J., Diaz, M., and Cleries, R. (2004). Primary liver cancer: worldwide incidence and trends. Gastroenterology 127, S5-S16.
Brandes, R.P., Weissmann, N., and Schroder, K. (2014). Nox family NADPH oxidases: Molecular mechanisms of activation. Free Radic Biol Med 76, 208-226.
Bressac, B., Kew, M., Wands, J., and Ozturk, M. (1991). Selective G to T mutations of p53 gene in hepatocellular carcinoma from southern Africa. Nature 350, 429-431.
Chang, C.P., Su, Y.C., Hu, C.W., and Lei, H.Y. (2013). TLR2-dependent selective autophagy regulates NF-kappaB lysosomal degradation in hepatoma-derived M2 macrophage differentiation. Cell Death Differ 20, 515-523.
Chen, M., Liu, Y., Varley, P., Chang, Y., He, X.X., Huang, H., Tang, D., Lotze, M.T., Lin, J., and Tsung, A. (2015). High-Mobility Group Box 1 Promotes Hepatocellular Carcinoma Progression through miR-21-Mediated Matrix Metalloproteinase Activity. Cancer Res 75, 1645-1656.
Chen, R.C., Yi, P.P., Zhou, R.R., Xiao, M.F., Huang, Z.B., Tang, D.L., Huang, Y., and Fan, X.G. (2014). The role of HMGB1-RAGE axis in migration and invasion of hepatocellular carcinoma cell lines. Mol Cell Biochem 390, 271-280.
Cheng, B.Q., Jia, C.Q., Liu, C.T., Lu, X.F., Zhong, N., Zhang, Z.L., Fan, W., and Li, Y.Q. (2008). Serum high mobility group box chromosomal protein 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Dig Liver Dis 40, 446-452.
Chowdhury, A.K., Watkins, T., Parinandi, N.L., Saatian, B., Kleinberg, M.E., Usatyuk, P.V., and Natarajan, V. (2005). Src-mediated tyrosine phosphorylation of p47phox in hyperoxia-induced activation of NADPH oxidase and generation of reactive oxygen species in lung endothelial cells. J Biol Chem 280, 20700-20711.
Cifani, N., Pompili, B., Anile, M., Patella, M., Diso, D., Venuta, F., Cimino, G., Quattrucci, S., Di Domenico, E.G., Ascenzioni, F., et al. (2013). Reactive-oxygen-species-mediated P. aeruginosa killing is functional in human cystic fibrosis macrophages. PLoS One 8, e71717.
Corrao, G., and Arico, S. (1998). Independent and combined action of hepatitis C virus infection and alcohol consumption on the risk of symptomatic liver cirrhosis. Hepatology 27, 914-919.
Corzo, C.A., Cotter, M.J., Cheng, P., Cheng, F., Kusmartsev, S., Sotomayor, E., Padhya, T., McCaffrey, T.V., McCaffrey, J.C., and Gabrilovich, D.I. (2009). Mechanism regulating reactive oxygen species in tumor-induced myeloid-derived suppressor cells. J Immunol 182, 5693-5701.
Deffert, C., Cachat, J., and Krause, K.H. (2014). Phagocyte NADPH oxidase, chronic granulomatous disease and mycobacterial infections. Cell Microbiol 16, 1168-1178.
Deretic, V., Delgado, M., Vergne, I., Master, S., De Haro, S., Ponpuak, M., and Singh, S. (2009). Autophagy in immunity against mycobacterium tuberculosis: a model system to dissect immunological roles of autophagy. Curr Top Microbiol Immunol 335, 169-188.
Dickinson, E., Tuncer, R., Nadler, E., Boyle, P., Alber, S., Watkins, S., and Ford, H. (1999). NOX, a novel nitric oxide scavenger, reduces bacterial translocation in rats after endotoxin challenge. Am J Physiol 277, G1281-1287.
Donato, F., Tagger, A., Gelatti, U., Parrinello, G., Boffetta, P., Albertini, A., Decarli, A., Trevisi, P., Ribero, M.L., Martelli, C., et al. (2002). Alcohol and hepatocellular carcinoma: the effect of lifetime intake and hepatitis virus infections in men and women. Am J Epidemiol 155, 323-331.
El-Serag, H.B. (2012).

. Gastroenterology 142, 1264-1273 e1261.
El-Tanani, M.K., Campbell, F.C., Kurisetty, V., Jin, D., McCann, M., and Rudland, P.S. (2006). The regulation and role of osteopontin in malignant transformation and cancer. Cytokine Growth Factor Rev 17, 463-474.
Erridge, C. (2010). Endogenous ligands of TLR2 and TLR4: agonists or assistants? J Leukoc Biol 87, 989-999.
Fattovich, G., Stroffolini, T., Zagni, I., and Donato, F. (2004). Hepatocellular carcinoma in cirrhosis: Incidence and risk factors. Gastroenterology 127, S35-S50.
Florese, R.H., Nagano-Fujii, M., Iwanaga, Y., Hidajat, R., and Hotta, H. (2002). Inhibition of protein synthesis by the nonstructural proteins NS4A and NS4B of hepatitis C virus. Virus Res 90, 119-131.
Fujita, N., Itoh, T., Omori, H., Fukuda, M., Noda, T., and Yoshimori, T. (2008). The Atg16L complex specifies the site of LC3 lipidation for membrane biogenesis in autophagy. Mol Biol Cell 19, 2092-2100.
Gardella, S., Andrei, C., Ferrera, D., Lotti, L.V., Torrisi, M.R., Bianchi, M.E., and Rubartelli, A. (2002). The nuclear protein HMGB1 is secreted by monocytes via a non-classical, vesicle-mediated secretory pathway. EMBO Rep 3, 995-1001.
Glick, D., Barth, S., and Macleod, K.F. (2010). Autophagy: cellular and molecular mechanisms. J Pathol 221, 3-12.
Gordon, S. (2003). Alternative activation of macrophages. Nat Rev Immunol 3, 23-35.
Greten, T.F., Manns, M.P., and Malek, N. (2009). [Sorafenib for the treatment of HCC--the beginning of a new era in the treatment of HCC]. Z Gastroenterol 47, 55-60.
Guo, X.L., Li, D., Hu, F., Song, J.R., Zhang, S.S., Deng, W.J., Sun, K., Zhao, Q.D., Xie, X.Q., Song, Y.J., et al. (2012). Targeting autophagy potentiates chemotherapy-induced apoptosis and proliferation inhibition in hepatocarcinoma cells. Cancer Lett 320, 171-179.
Huang, J., and Brumell, J.H. (2009). NADPH oxidases contribute to autophagy regulation. Autophagy 5, 887-889.
Itakura, E., and Mizushima, N. (2010). Characterization of autophagosome formation site by a hierarchical analysis of mammalian Atg proteins. Autophagy 6, 764-776.
Javaherian, K., Liu, J.F., and Wang, J.C. (1978). Nonhistone proteins HMG1 and HMG2 change the DNA helical structure. Science 199, 1345-1346.
Jiang, H., Harris, M.B., and Rothman, P. (2000). IL-4/IL-13 signaling beyond JAK/STAT. J Allergy Clin Immunol 105, 1063-1070.
Jiang, S., Dupont, N., Castillo, E.F., and Deretic, V. (2013). Secretory versus degradative autophagy: unconventional secretion of inflammatory mediators. Journal of innate immunity 5, 471-479.
Jiang, W., Wang, Z., Li, X., Fan, X., and Duan, Y. (2012). High-mobility group box 1 is associated with clinicopathologic features in patients with hepatocellular carcinoma. Pathol Oncol Res 18, 293-298.
Joyce, J.A., and Pollard, J.W. (2009). Microenvironmental regulation of metastasis. Nat Rev Cancer 9, 239-252.
Kondo, Y., Kanzawa, T., Sawaya, R., and Kondo, S. (2005). The role of autophagy in cancer development and response to therapy. Nat Rev Cancer 5, 726-734.
Kostova, N., Zlateva, S., Ugrinova, I., and Pasheva, E. (2010). The expression of HMGB1 protein and its receptor RAGE in human malignant tumors. Mol Cell Biochem 337, 251-258.
Kwun, H.J., Jung, E.Y., Ahn, J.Y., Lee, M.N., and Jang, K.L. (2001). p53-dependent transcriptional repression of p21(waf1) by hepatitis C virus NS3. J Gen Virol 82, 2235-2241.
Lan, K.H., Sheu, M.L., Hwang, S.J., Yen, S.H., Chen, S.Y., Wu, J.C., Wang, Y.J., Kato, N., Omata, M., Chang, F.Y., et al. (2002). HCV NS5A interacts with p53 and inhibits p53-mediated apoptosis. Oncogene 21, 4801-4811.
Lee, I.T., Wang, S.W., Lee, C.W., Chang, C.C., Lin, C.C., Luo, S.F., and Yang, C.M. (2008). Lipoteichoic acid induces HO-1 expression via the TLR2/MyD88/c-Src/NADPH oxidase pathway and Nrf2 in human tracheal smooth muscle cells. J Immunol 181, 5098-5110.
Lee, M.N., Jung, E.Y., Kwun, H.J., Jun, H.K., Yu, D.Y., Choi, Y.H., and Jang, K.L. (2002). Hepatitis C virus core protein represses the p21 promoter through inhibition of a TGF-beta pathway. J Gen Virol 83, 2145-2151.
Lin, E.Y., Li, J.F., Gnatovskiy, L., Deng, Y., Zhu, L., Grzesik, D.A., Qian, H., Xue, X.N., and Pollard, J.W. (2006). Macrophages regulate the angiogenic switch in a mouse model of breast cancer. Cancer Res 66, 11238-11246.
Martinez, F.O., and Gordon, S. (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep 6, 13.
Martinez, F.O., Helming, L., and Gordon, S. (2009). Alternative activation of macrophages: an immunologic functional perspective. Annu Rev Immunol 27, 451-483.
Matarrese, P., Fusco, O., Tinari, N., Natoli, C., Liu, F.T., Semeraro, M.L., Malorni, W., and Iacobelli, S. (2000). Galectin-3 overexpression protects from apoptosis by improving cell adhesion properties. Int J Cancer 85, 545-554.
Matsunaga, K., Saitoh, T., Tabata, K., Omori, H., Satoh, T., Kurotori, N., Maejima, I., Shirahama-Noda, K., Ichimura, T., Isobe, T., et al. (2009). Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol 11, 385-396.
Matteoni, C.A., Younossi, Z.M., Gramlich, T., Boparai, N., Liu, Y.C., and McCullough, A.J. (1999). Nonalcoholic fatty liver disease: a spectrum of clinical and pathological severity. Gastroenterology 116, 1413-1419.
Mbeunkui, F., and Johann, D.J., Jr. (2009). Cancer and the tumor microenvironment: a review of an essential relationship. Cancer Chemother Pharmacol 63, 571-582.
Mitroulis, I., Kourtzelis, I., Kambas, K., Chrysanthopoulou, A., and Ritis, K. (2011). Evidence for the involvement of mTOR inhibition and basal autophagy in familial Mediterranean fever phenotype. Hum Immunol 72, 135-138.
Mittal, S., and El-Serag, H.B. (2013). Epidemiology of hepatocellular carcinoma: consider the population. J Clin Gastroenterol 47 Suppl, S2-6.
Movahedi, K., Laoui, D., Gysemans, C., Baeten, M., Stange, G., Van den Bossche, J., Mack, M., Pipeleers, D., In't Veld, P., De Baetselier, P., et al. (2010). Different tumor microenvironments contain functionally distinct subsets of macrophages derived from Ly6C(high) monocytes. Cancer Res 70, 5728-5739.
Mroue, R., and Bissell, M.J. (2013). Three-dimensional cultures of mouse mammary epithelial cells. Methods Mol Biol 945, 221-250.
Munakata, T., Nakamura, M., Liang, Y., Li, K., and Lemon, S.M. (2005). Down-regulation of the retinoblastoma tumor suppressor by the hepatitis C virus NS5B RNA-dependent RNA polymerase. Proc Natl Acad Sci U S A 102, 18159-18164.
Nagasue, N., Uchida, M., Makino, Y., Takemoto, Y., Yamanoi, A., Hayashi, T., Chang, Y.C., Kohno, H., Nakamura, T., and Yukaya, H. (1993). Incidence and factors associated with intrahepatic recurrence following resection of hepatocellular carcinoma. Gastroenterology 105, 488-494.
Nakatogawa, H., Suzuki, K., Kamada, Y., and Ohsumi, Y. (2009). Dynamics and diversity in autophagy mechanisms: lessons from yeast. Nat Rev Mol Cell Biol 10, 458-467.
O'Shea, J.J., Pesu, M., Borie, D.C., and Changelian, P.S. (2004). A new modality for immunosuppression: targeting the JAK/STAT pathway. Nat Rev Drug Discov 3, 555-564.
Palumbo, R., Sampaolesi, M., De Marchis, F., Tonlorenzi, R., Colombetti, S., Mondino, A., Cossu, G., and Bianchi, M.E. (2004). Extracellular HMGB1, a signal of tissue damage, induces mesoangioblast migration and proliferation. J Cell Biol 164, 441-449.
Papale, F., Cafiero, G., Grimaldi, A., Marino, G., Rosso, F., Mian, C., Barollo, S., Pennelli, G., Sorrenti, S., De Antoni, E., et al. (2013). Galectin-3 expression in thyroid fine needle cytology (t-FNAC) uncertain cases: validation of molecular markers and technology innovation. J Cell Physiol 228, 968-974.
Park, J.S., Svetkauskaite, D., He, Q., Kim, J.Y., Strassheim, D., Ishizaka, A., and Abraham, E. (2004). Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein. J Biol Chem 279, 7370-7377.
Peng, Z., Zhang, Y., Gu, W., Wang, Z., Li, D., Zhang, F., Qiu, G., and Xie, K. (2005). Integration of the hepatitis B virus X fragment in hepatocellular carcinoma and its effects on the expression of multiple molecules: a key to the cell cycle and apoptosis. Int J Oncol 26, 467-473.
Piao, Y.J., Seo, Y.H., Hong, F., Kim, J.H., Kim, Y.J., Kang, M.H., Kim, B.S., Jo, S.A., Jo, I., Jue, D.M., et al. (2005). Nox 2 stimulates muscle differentiation via NF-kappaB/iNOS pathway. Free Radic Biol Med 38, 989-1001.
Pizzolla, A., Hultqvist, M., Nilson, B., Grimm, M.J., Eneljung, T., Jonsson, I.M., Verdrengh, M., Kelkka, T., Gjertsson, I., Segal, B.H., et al. (2012). Reactive oxygen species produced by the NADPH oxidase 2 complex in monocytes protect mice from bacterial infections. J Immunol 188, 5003-5011.
Pollard, J.W. (2004). Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer 4, 71-78.
Qian, B., Deng, Y., Im, J.H., Muschel, R.J., Zou, Y., Li, J., Lang, R.A., and Pollard, J.W. (2009). A distinct macrophage population mediates metastatic breast cancer cell extravasation, establishment and growth. PLoS One 4, e6562.
Qureshi, K., and Abrams, G.A. (2007). Metabolic liver disease of obesity and role of adipose tissue in the pathogenesis of nonalcoholic fatty liver disease. World J Gastroenterol 13, 3540-3553.
Reggiori, F., and Klionsky, D.J. (2002). Autophagy in the eukaryotic cell. Eukaryot Cell 1, 11-21.
Romao, S., Gasser, N., Becker, A.C., Guhl, B., Bajagic, M., Vanoaica, D., Ziegler, U., Roesler, J., Dengjel, J., Reichenbach, J., et al. (2013). Autophagy proteins stabilize pathogen-containing phagosomes for prolonged MHC II antigen processing. J Cell Biol 203, 757-766.
Rudland, P.S., Platt-Higgins, A., El-Tanani, M., De Silva Rudland, S., Barraclough, R., Winstanley, J.H., Howitt, R., and West, C.R. (2002). Prognostic significance of the metastasis-associated protein osteopontin in human breast cancer. Cancer Res 62, 3417-3427.
Ryder, S.D., and British Society of, G. (2003). Guidelines for the diagnosis and treatment of hepatocellular carcinoma (HCC) in adults. Gut 52 Suppl 3, iii1-8.
Sardina, J.L., Lopez-Ruano, G., Sanchez-Abarca, L.I., Perez-Simon, J.A., Gaztelumendi, A., Trigueros, C., Llanillo, M., Sanchez-Yague, J., and Hernandez-Hernandez, A. (2010). p22phox-dependent NADPH oxidase activity is required for megakaryocytic differentiation. Cell Death Differ 17, 1842-1854.
Scaffidi, P., Misteli, T., and Bianchi, M.E. (2002). Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature 418, 191-195.
Scherz-Shouval, R., and Elazar, Z. (2011). Regulation of autophagy by ROS: physiology and pathology. Trends Biochem Sci 36, 30-38.
Sica, A., and Bronte, V. (2007). Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest 117, 1155-1166.
Sitia, G., Aiolfi, R., Di Lucia, P., Mainetti, M., Fiocchi, A., Mingozzi, F., Esposito, A., Ruggeri, Z.M., Chisari, F.V., Iannacone, M., et al. (2012). Antiplatelet therapy prevents hepatocellular carcinoma and improves survival in a mouse model of chronic hepatitis B. Proc Natl Acad Sci U S A 109, E2165-2172.
Solinas, G., Germano, G., Mantovani, A., and Allavena, P. (2009). Tumor-associated macrophages (TAM) as major players of the cancer-related inflammation. J Leukoc Biol 86, 1065-1073.
Su, I.J., Hsieh, W.C., Tsai, H.W., and Wu, H.C. (2013). Chemoprevention and novel therapy for hepatocellular carcinoma associated with chronic hepatitis B virus infection. Hepatobiliary Surg Nutr 2, 37-39.
Su, I.J., Wang, L.H., Hsieh, W.C., Wu, H.C., Teng, C.F., Tsai, H.W., and Huang, W. (2014). The emerging role of hepatitis B virus pre-S2 deletion mutant proteins in HBV tumorigenesis. J Biomed Sci 21, 98.
Sumimoto, H., Miyano, K., and Takeya, R. (2005). Molecular composition and regulation of the Nox family NAD(P)H oxidases. Biochem Biophys Res Commun 338, 677-686.
Sun, B., and Karin, M. (2008). NF-kappaB signaling, liver disease and hepatoprotective agents. Oncogene 27, 6228-6244.
Takeshige, K., Baba, M., Tsuboi, S., Noda, T., and Ohsumi, Y. (1992). Autophagy in yeast demonstrated with proteinase-deficient mutants and conditions for its induction. J Cell Biol 119, 301-311.
Tang, X., Mo, C., Wang, Y., Wei, D., and Xiao, H. (2013). Anti-tumour strategies aiming to target tumour-associated macrophages. Immunology 138, 93-104.
The Journal of immunologyAdami, H.O., Hsing, A.W., McLaughlin, J.K., Trichopoulos, D., Hacker, D., Ekbom, A., and Persson, I. (1992). Alcoholism and liver cirrhosis in the etiology of primary liver cancer. Int J Cancer 51, 898-902.
Tian, J., Avalos, A.M., Mao, S.Y., Chen, B., Senthil, K., Wu, H., Parroche, P., Drabic, S., Golenbock, D., Sirois, C., et al. (2007). Toll-like receptor 9-dependent activation by DNA-containing immune complexes is mediated by HMGB1 and RAGE. Nat Immunol 8, 487-496.
Tredan, O., Galmarini, C.M., Patel, K., and Tannock, I.F. (2007). Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst 99, 1441-1454.
Tuck, A.B., and Chambers, A.F. (2001). The role of osteopontin in breast cancer: clinical and experimental studies. J Mammary Gland Biol Neoplasia 6, 419-429.
Utzschneider, K.M., and Kahn, S.E. (2006). Review: The role of insulin resistance in nonalcoholic fatty liver disease. J Clin Endocrinol Metab 91, 4753-4761.
Villanueva, A., and Llovet, J.M. (2011). Targeted therapies for hepatocellular carcinoma. Gastroenterology 140, 1410-1426.
Villar, S., Ortiz-Cuaran, S., Abedi-Ardekani, B., Gouas, D., Nogueira da Costa, A., Plymoth, A., Khuhaprema, T., Kalalak, A., Sangrajrang, S., Friesen, M.D., et al. (2012). Aflatoxin-induced TP53 R249S mutation in hepatocellular carcinoma in Thailand: association with tumors developing in the absence of liver cirrhosis. PLoS One 7, e37707.
Virgin, H.W., and Levine, B. (2009). Autophagy genes in immunity. Nat Immunol 10, 461-470.
Wang, W., Xu, G.L., Jia, W.D., Ma, J.L., Li, J.S., Ge, Y.S., Ren, W.H., Yu, J.H., and Liu, W.B. (2009). Ligation of TLR2 by versican: a link between inflammation and metastasis. Arch Med Res 40, 321-323.
Weber, G.F. (2001). The metastasis gene osteopontin: a candidate target for cancer therapy. Biochim Biophys Acta 1552, 61-85.
Yang, H., Antoine, D.J., Andersson, U., and Tracey, K.J. (2013). The many faces of HMGB1: molecular structure-functional activity in inflammation, apoptosis, and chemotaxis. J Leukoc Biol 93, 865-873.
Yang, M., Shao, J.H., Miao, Y.J., Cui, W., Qi, Y.F., Han, J.H., Lin, X., and Du, J. (2014). Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization. Cell Death Differ 21, 1290-1302.
Yang, Z., and Klionsky, D.J. (2009). An overview of the molecular mechanism of autophagy. Curr Top Microbiol Immunol 335, 1-32.
Zhang, Y., Choksi, S., Chen, K., Pobezinskaya, Y., Linnoila, I., and Liu, Z.G. (2013). ROS play a critical role in the differentiation of alternatively activated macrophages and the occurrence of tumor-associated macrophages. Cell Res 23, 898-914.
Zheng, Y., Cai, Z., Wang, S., Zhang, X., Qian, J., Hong, S., Li, H., Wang, M., Yang, J., and Yi, Q. (2009). Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug-induced apoptosis. Blood 114, 3625-3628.