肝癌在全世界癌症相關死亡原因中排名第三。大部分的肝細胞癌患者處於疾病晚期，而晚期病患的血管過度增生與血管異常是導致手術無法進行的常見原因，所以大部分病患會接受血管生成之標靶藥物sorafenib的治療；然而它的效果受限於病患產生的抗藥性。有關sorafenib抗藥性產生的原因，多篇研究已指出癌症幹細胞可能扮演很重要的角色，但針對癌症幹細胞的治療卻很困難。近來很多研究將重點放在腫瘤微環境與癌症的相互作用，而其中的腫瘤相關巨噬細胞會調節肝細胞癌的血管生成、細胞增殖與轉移，甚至調節肝癌幹細胞及sorafenib的抗藥性，只是其中的機制卻還不清楚。我們在具抗藥的病患檢體中，發現有較高的癌症幹細胞與腫瘤相關巨噬細胞的表達。這些數據顯示了癌症幹細胞與腫瘤相關巨噬細胞的存在與sorafenib的抗藥性有相關性。在體外共培養的系統中，我們也證實腫瘤相關巨噬細胞的參與，會增加肝細胞癌細胞對sorafenib的抗藥性和癌症幹細胞的表達。透過ELISA分析細胞因子，觀察到相較於單獨培養肝癌細胞，CXCL1及CXCL2在共培養的培養液中有更高的表達。接著我們也證實了腫瘤相關巨噬細胞可透過分泌CXCL1和CXCL2而刺激肝癌細胞的CXCR1/2下游的路徑包括ERK，AKT/mTOR，STAT3，進而增加癌症幹細胞的數量和sorafenib抗藥性。分別使用以上三條路徑的抑制劑能有效減少癌症幹細胞的數量以及增加對sorafenib的敏感度。而使用CXCR1/2的抑制劑SB225002則有更顯著的效果。SB225002在胰臟癌、胃癌及肺癌已是被證實能達到治療效果的藥物。用於肝細胞癌的治療，或是與sorafenib合併使用，或許能成為一個有潛力的方向。

Liver cancer is the third leading cause of cancer-related death worldwide. Most HCC patients are diagnosed at the advanced stage. Excessive blood vessel proliferation and abnormal blood vessels in advanced HCC makes surgery impossible. Sorafenib is a targeted therapeutic drug for angiogenesis, frequently used in HCC treatment; however, resistance to this drug inevitably develops. Cancer stem cells (CSCs) reportedly play a critical role in causing sorafenib resistance, suggesting the importance of targeting CSCs. Recent studies have focused on the interaction between tumor microenvironment and cancer, and found that TAMs can regulate angiogenesis, cell proliferation, metastasis, and even the resistance to sorafenib and CSC activity in HCC. However, the mechanism is unclear. In this study, we found higher expression of CSCs and TAMs in sorafenib nonresponsive (SNR) patients, suggesting the correlation of sorafenib resistance with CSCs and TAMs. In the in vitro co-culture system, we also saw that TAMs increased levels of CSCs but decreased sorafenib-induced apoptosis. Following analysis of cytokines by ELISA, higher expression of CXCL1 and CXCL2 was found in the conditioned medium of HCC/TAM co-culture than that of HCC mono-culture. We could also see that TAMs stimulated the CXCR1/2 downstream pathways including ERK, AKT/mTOR, and STAT3 in HCC cells by secreting CXCL1 and CXCL2, thereby increasing the level of CSCs, Bcl-2 expression, and sorafenib resistance. Using the specific inhibitors against the above three pathways reduced the level of CSCs and increase the sensitivity to sorafenib. The use of CXCR1/2 inhibitor SB225002 that has been proven to achieve therapeutic effects in various cancers had a more significant effect. For the treatment of HCC, SB225002 alone or in combination with sorafenib may be a good treatment direction in the future.

Adams, J. M., & Strasser, A. (2008). Is Tumor Growth Sustained by Rare Cancer Stem Cells or Dominant Clones? Cancer Res, 68(11), 4018-4021. doi:10.1158/0008-5472.can-07-6334
Allaire, M., Goumard, C., Lim, C., Le Cleach, A., Wagner, M., & Scatton, O. (2020). New frontiers in liver resection for hepatocellular carcinoma. JHEP Reports, 2(4), 100134. doi:10.1016/j.jhepr.2020.100134
Angelucci, A. (2019). Targeting Tyrosine Kinases in Cancer: Lessons for an Effective Targeted Therapy in the Clinic. Cancers (Basel), 11(4). doi:10.3390/cancers11040490
Ankoma-Sey, V., Matli, M., Chang, K. B., Lalazar, A., Donner, D. B., Wong, L., . . . Friedman, S. L. (1998). Coordinated induction of VEGF receptors in mesenchymal cell types during rat hepatic wound healing. Oncogene, 17(1), 115-121. doi:10.1038/sj.onc.1201912
Biswas, S. K., & Mantovani, A. (2010). Macrophage plasticity and interaction with lymphocyte subsets: cancer as a paradigm. Nature Immunology, 11(10), 889-896. doi:10.1038/ni.1937
Blachier, M., Leleu, H., Peck-Radosavljevic, M., Valla, D. C., & Roudot-Thoraval, F. (2013). The burden of liver disease in Europe: a review of available epidemiological data. J Hepatol, 58(3), 593-608. doi:10.1016/j.jhep.2012.12.005
Brunetti, O., Gnoni, A., Licchetta, A., Longo, V., Calabrese, A., Argentiero, A., . . . Silvestris, N. (2019). Predictive and Prognostic Factors in HCC Patients Treated with Sorafenib. Medicina (Kaunas), 55(10). doi:10.3390/medicina55100707
Burger, M., Hartmann, T., Burger, J. A., & Schraufstatter, I. (2005). KSHV-GPCR and CXCR2 transforming capacity and angiogenic responses are mediated through a JAK2-STAT3-dependent pathway. Oncogene, 24(12), 2067-2075. doi:10.1038/sj.onc.1208442
Burrel, M., Reig, M., Forner, A., Barrufet, M., de Lope, C. R., Tremosini, S., . . . Bruix, J. (2012). Survival of patients with hepatocellular carcinoma treated by transarterial chemoembolisation (TACE) using Drug Eluting Beads. Implications for clinical practice and trial design. J Hepatol, 56(6), 1330-1335. doi:10.1016/j.jhep.2012.01.008
Castells, M., Thibault, B., Mery, E., Golzio, M., Pasquet, M., Hennebelle, I., . . . Couderc, B. (2012). Ovarian ascites-derived Hospicells promote angiogenesis via activation of macrophages. Cancer Letters, 326(1), 59-68. doi:https://doi.org/10.1016/j.canlet.2012.07.020
Cazejust, J., Bessoud, B., Colignon, N., Garcia-Alba, C., Planché, O., & Menu, Y. (2014). Hepatocellular carcinoma vascularization: From the most common to the lesser known arteries. Diagnostic and Interventional Imaging, 95(1), 27-36. doi:https://doi.org/10.1016/j.diii.2013.04.015
Chawla, A. (2010). Control of macrophage activation and function by PPARs. Circ Res, 106(10), 1559-1569. doi:10.1161/circresaha.110.216523
Chen, J., Jin, R., Zhao, J., Liu, J., Ying, H., Yan, H., . . . Cai, X. (2015). Potential molecular, cellular and microenvironmental mechanism of sorafenib resistance in hepatocellular carcinoma. Cancer Letters, 367(1), 1-11. doi:https://doi.org/10.1016/j.canlet.2015.06.019
Chen, M. C., Baskaran, R., Lee, N. H., Hsu, H. H., Ho, T. J., Tu, C. C., . . . Huang, C. Y. (2019). CXCL2/CXCR2 axis induces cancer stem cell characteristics in CPT-11-resistant LoVo colon cancer cells via Gαi-2 and Gαq/11. J Cell Physiol, 234(7), 11822-11834. doi:10.1002/jcp.27891
Chen, X., Chen, R., Jin, R., & Huang, Z. (2020). The role of CXCL chemokine family in the development and progression of gastric cancer. Int J Clin Exp Pathol, 13(3), 484-492.
Chen, X., Lingala, S., Khoobyari, S., Nolta, J., Zern, M. A., & Wu, J. (2011). Epithelial mesenchymal transition and hedgehog signaling activation are associated with chemoresistance and invasion of hepatoma subpopulations. J Hepatol, 55(4), 838-845. doi:10.1016/j.jhep.2010.12.043
Chen, Y., Wen, H., Zhou, C., Su, Q., Lin, Y., Xie, Y., . . . Wang, C. (2019). TNF-α derived from M2 tumor-associated macrophages promotes epithelial-mesenchymal transition and cancer stemness through the Wnt/β-catenin pathway in SMMC-7721 hepatocellular carcinoma cells. Exp Cell Res, 378(1), 41-50. doi:10.1016/j.yexcr.2019.03.005
Cheng, Y., Ma, X.-l., Wei, Y.-q., & Wei, X.-W. (2019). Potential roles and targeted therapy of the CXCLs/CXCR2 axis in cancer and inflammatory diseases. Biochimica et Biophysica Acta (BBA) - Reviews on Cancer, 1871(2), 289-312. doi:https://doi.org/10.1016/j.bbcan.2019.01.005
Cordo', V., van der Zwet, J. C. G., Canté-Barrett, K., Pieters, R., & Meijerink, J. P. P. (2021). T-cell Acute Lymphoblastic Leukemia: A Roadmap to Targeted Therapies. Blood Cancer Discovery, 2(1), 19-31. doi:10.1158/2643-3230.bcd-20-0093
Costanzo, G. G. D., Tortora, R., Opramolla, A., & Guarracino, M. (2018). Thermal ablation of large unresectable hepatocellular carcinoma in cirrhotic patients. Hepatoma Research, 4, 53. doi:10.20517/2394-5079.2018.56
Daher, S., Massarwa, M., Benson, A. A., & Khoury, T. (2018). Current and Future Treatment of Hepatocellular Carcinoma: An Updated Comprehensive Review. J Clin Transl Hepatol, 6(1), 69-78. doi:10.14218/jcth.2017.00031
Damiano, J. S., Cress, A. E., Hazlehurst, L. A., Shtil, A. A., & Dalton, W. S. (1999). Cell adhesion mediated drug resistance (CAM-DR): role of integrins and resistance to apoptosis in human myeloma cell lines. Blood, 93(5), 1658-1667.
Di Costanzo, G. G., Francica, G., & Pacella, C. M. (2014). Laser ablation for small hepatocellular carcinoma: State of the art and future perspectives. World J Hepatol, 6(10), 704-715. doi:10.4254/wjh.v6.i10.704
Dick, J. E. (2009). Looking ahead in cancer stem cell research. Nature Biotechnology, 27(1), 44-46. doi:10.1038/nbt0109-44
Dong, N., Shi, X., Wang, S., Gao, Y., Kuang, Z., Xie, Q., . . . Li, J. L. (2019). M2 macrophages mediate sorafenib resistance by secreting HGF in a feed-forward manner in hepatocellular carcinoma. Br J Cancer, 121(1), 22-33. doi:10.1038/s41416-019-0482-x
Doyle, A. G., Herbein, G., Montaner, L. J., Minty, A. J., Caput, D., Ferrara, P., & Gordon, S. (1994). Interleukin-13 alters the activation state of murine macrophages in vitro: comparison with interleukin-4 and interferon-gamma. Eur J Immunol, 24(6), 1441-1445. doi:10.1002/eji.1830240630
Du, B., & Shim, J. S. (2016). Targeting Epithelial-Mesenchymal Transition (EMT) to Overcome Drug Resistance in Cancer. Molecules, 21(7). doi:10.3390/molecules21070965
EASL-EORTC clinical practice guidelines: management of hepatocellular carcinoma. (2012). J Hepatol, 56(4), 908-943. doi:10.1016/j.jhep.2011.12.001
El-Serag, H. B. (2011). Hepatocellular carcinoma. N Engl J Med, 365(12), 1118-1127. doi:10.1056/NEJMra1001683
Fan, Q. M., Jing, Y. Y., Yu, G. F., Kou, X. R., Ye, F., Gao, L., . . . Wei, L. X. (2014). Tumor-associated macrophages promote cancer stem cell-like properties via transforming growth factor-beta1-induced epithelial-mesenchymal transition in hepatocellular carcinoma. Cancer Lett, 352(2), 160-168. doi:10.1016/j.canlet.2014.05.008
Fernando, J., Malfettone, A., Cepeda, E. B., Vilarrasa-Blasi, R., Bertran, E., Raimondi, G., . . . Fabregat, I. (2015). A mesenchymal-like phenotype and expression of CD44 predict lack of apoptotic response to sorafenib in liver tumor cells. Int J Cancer, 136(4), E161-E172. doi:https://doi.org/10.1002/ijc.29097
Fernández, M., Semela, D., Bruix, J., Colle, I., Pinzani, M., & Bosch, J. (2009). Angiogenesis in liver disease. J Hepatol, 50(3), 604-620. doi:10.1016/j.jhep.2008.12.011
Ferrante, C. J., Pinhal-Enfield, G., Elson, G., Cronstein, B. N., Hasko, G., Outram, S., & Leibovich, S. J. (2013). The adenosine-dependent angiogenic switch of macrophages to an M2-like phenotype is independent of interleukin-4 receptor alpha (IL-4Rα) signaling. Inflammation, 36(4), 921-931. doi:10.1007/s10753-013-9621-3
Flecken, T., Schmidt, N., Hild, S., Gostick, E., Drognitz, O., Zeiser, R., . . . Thimme, R. (2014). Immunodominance and functional alterations of tumor-associated antigen-specific CD8+ T-cell responses in hepatocellular carcinoma. Hepatology, 59(4), 1415-1426. doi:10.1002/hep.26731
Frenzel, A., Grespi, F., Chmelewskij, W., & Villunger, A. (2009). Bcl2 family proteins in carcinogenesis and the treatment of cancer. Apoptosis, 14(4), 584-596. doi:10.1007/s10495-008-0300-z
Galmiche, A., Ezzoukhry, Z., François, C., Louandre, C., Sabbagh, C., Nguyen-Khac, E., . . . Chatelain, D. (2010). BAD, a Proapoptotic Member of the BCL2 Family, Is a Potential Therapeutic Target in Hepatocellular Carcinoma. Molecular Cancer Research, 8(8), 1116. doi:10.1158/1541-7786.MCR-10-0029
Gazit, A., Osherov, N., Posner, I., Yaish, P., Poradosu, E., Gilon, C., & Levitzki, A. (1991). Tyrphostins. 2. Heterocyclic and alpha-substituted benzylidenemalononitrile tyrphostins as potent inhibitors of EGF receptor and ErbB2/neu tyrosine kinases. J Med Chem, 34(6), 1896-1907. doi:10.1021/jm00110a022
Gazit, A., Yaish, P., Gilon, C., & Levitzki, A. (1989). Tyrphostins I: synthesis and biological activity of protein tyrosine kinase inhibitors. J Med Chem, 32(10), 2344-2352. doi:10.1021/jm00130a020
Gerber, D. E. (2008). Targeted therapies: a new generation of cancer treatments. Am Fam Physician, 77(3), 311-319.
Giannelli, G., Rani, B., Dituri, F., Cao, Y., & Palasciano, G. (2014). Moving towards personalised therapy in patients with hepatocellular carcinoma: The role of the microenvironment. Gut, 63. doi:10.1136/gutjnl-2014-307323
Gobeil, L. A., Lodge, R., & Tremblay, M. J. (2012). Differential HIV-1 endocytosis and susceptibility to virus infection in human macrophages correlate with cell activation status. J Virol, 86(19), 10399-10407. doi:10.1128/jvi.01051-12
Gordeeva, O. (2019). TGFβ Family Signaling Pathways in Pluripotent and Teratocarcinoma Stem Cells' Fate Decisions: Balancing Between Self-Renewal, Differentiation, and Cancer. Cells, 8(12). doi:10.3390/cells8121500
Gordon, S., & Taylor, P. R. (2005). Monocyte and macrophage heterogeneity. Nature Reviews Immunology, 5(12), 953-964. doi:10.1038/nri1733
Gratchev, A. (2017). TGF-β signalling in tumour associated macrophages. Immunobiology, 222(1), 75-81. doi:10.1016/j.imbio.2015.11.016
Han, J., Won, M., Kim, J. H., Jung, E., Min, K., Jangili, P., & Kim, J. S. (2020). Cancer stem cell-targeted bio-imaging and chemotherapeutic perspective. Chem Soc Rev, 49(22), 7856-7878. doi:10.1039/d0cs00379d
Hellerbrand, C., Hartmann, A., Richter, G., Knöll, A., Wiest, R., Schölmerich, J., & Lock, G. (2001). Hepatocellular Carcinoma in Southern Germany: Epidemiological and Clinicopathological Characteristics and Risk Factors. Digestive Diseases, 19(4), 345-351. doi:10.1159/000050702
Helmy, K. Y., Katschke, K. J., Jr., Gorgani, N. N., Kljavin, N. M., Elliott, J. M., Diehl, L., . . . van Lookeren Campagne, M. (2006). CRIg: a macrophage complement receptor required for phagocytosis of circulating pathogens. Cell, 124(5), 915-927. doi:10.1016/j.cell.2005.12.039
Hernandez-Gea, V., Toffanin, S., Friedman, S. L., & Llovet, J. M. (2013). Role of the microenvironment in the pathogenesis and treatment of hepatocellular carcinoma. Gastroenterology, 144(3), 512-527. doi:10.1053/j.gastro.2013.01.002
Hindson, J. (2020). Combined TACE and sorafenib for HCC treatment. Nature Reviews Gastroenterology & Hepatology, 17(2), 66-66. doi:10.1038/s41575-020-0265-0
Hu, Y., Yagüe, E., Zhao, J., Wang, L., Bai, J., Yang, Q., . . . Zhang, J. (2018). Sabutoclax, pan-active BCL-2 protein family antagonist, overcomes drug resistance and eliminates cancer stem cells in breast cancer. Cancer Lett, 423, 47-59. doi:10.1016/j.canlet.2018.02.036
Huang, A., Yang, X.-R., Chung, W.-Y., Dennison, A. R., & Zhou, J. (2020). Targeted therapy for hepatocellular carcinoma. Signal Transduction and Targeted Therapy, 5(1), 146. doi:10.1038/s41392-020-00264-x
Huang, G., Li, S., Zhang, Y., Zhou, X., & Chen, W. (2020). Vicenin-2 is a novel inhibitor of STAT3 signaling pathway in human hepatocellular carcinoma. Journal of Functional Foods, 69, 103921. doi:https://doi.org/10.1016/j.jff.2020.103921
Huang, P., Qiu, J., Li, B., Hong, J., Lu, C., Wang, L., . . . Yuan, Y. (2011). Role of Sox2 and Oct4 in predicting survival of hepatocellular carcinoma patients after hepatectomy. Clinical Biochemistry, 44(8), 582-589. doi:https://doi.org/10.1016/j.clinbiochem.2011.02.012
Huang, P. Z., Lu, C. L., Li, B. K., Hong, J., Huang, L., Wang, L., . . . Yuan, Y. F. (2010). [OCT4 expression in hepatocellular carcinoma and its clinical significance]. Chin J Cancer, 29(1), 111-116. doi:10.5732/cjc.009.10232
Ingangi, V., Minopoli, M., Ragone, C., Motti, M. L., & Carriero, M. V. (2019). Role of Microenvironment on the Fate of Disseminating Cancer Stem Cells. Frontiers in Oncology, 9(82). doi:10.3389/fonc.2019.00082
Kalluri, R., & Weinberg, R. A. (2009). The basics of epithelial-mesenchymal transition. J Clin Invest, 119(6), 1420-1428. doi:10.1172/jci39104
Kapse-Mistry, S., Govender, T., Srivastava, R., & Yergeri, M. (2014). Nanodrug delivery in reversing multidrug resistance in cancer cells. Frontiers in Pharmacology, 5(159). doi:10.3389/fphar.2014.00159
Kim, J., Chu, J., Shen, X., Wang, J., & Orkin, S. H. (2008). An Extended Transcriptional Network for Pluripotency of Embryonic Stem Cells. Cell, 132(6), 1049-1061. doi:https://doi.org/10.1016/j.cell.2008.02.039
Knall, C., Worthen, G. S., & Johnson, G. L. (1997). Interleukin 8-stimulated phosphatidylinositol-3-kinase activity regulates the migration of human neutrophils independent of extracellular signal-regulated kinase and p38 mitogen-activated protein kinases. Proc Natl Acad Sci U S A, 94(7), 3052-3057. doi:10.1073/pnas.94.7.3052
Kudo, M., Finn, R. S., Qin, S., Han, K. H., Ikeda, K., Piscaglia, F., . . . Cheng, A. L. (2018). Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: a randomised phase 3 non-inferiority trial. Lancet, 391(10126), 1163-1173. doi:10.1016/s0140-6736(18)30207-1
Labadie, K., Sullivan, K., & Park, J. O. (2018). Surgical Resection in HCC.
Lai, Y. S., Putra, R., Aui, S. P., & Chang, K. T. (2018). M2(C) Polarization by Baicalin Enhances Efferocytosis via Upregulation of MERTK Receptor. Am J Chin Med, 46(8), 1899-1914. doi:10.1142/s0192415x18500957
Lai, Y. S., Wahyuningtyas, R., Aui, S. P., & Chang, K. T. (2019). Autocrine VEGF signalling on M2 macrophages regulates PD-L1 expression for immunomodulation of T cells. J Cell Mol Med, 23(2), 1257-1267. doi:10.1111/jcmm.14027
Larionova, I., Cherdyntseva, N., Liu, T., Patysheva, M., Rakina, M., & Kzhyshkowska, J. (2019). Interaction of tumor-associated macrophages and cancer chemotherapy. Oncoimmunology, 8(7), 1596004. doi:10.1080/2162402x.2019.1596004
Lau, W. Y., Leung, T. W., Yu, S. C., & Ho, S. K. (2003). Percutaneous local ablative therapy for hepatocellular carcinoma: a review and look into the future. Annals of surgery, 237(2), 171-179. doi:10.1097/01.sla.0000048443.71734.bf
Le Naour, A., Prat, M., Thibault, B., Mével, R., Lemaitre, L., Leray, H., . . . Couderc, B. (2019). Tumor cells educate mesenchymal stromal cells to release chemoprotective and immunomodulatory factors. Journal of Molecular Cell Biology, 12(3), 202-215. doi:10.1093/jmcb/mjz090
Leber, B., Lin, J., & Andrews, D. W. (2007). Embedded together: the life and death consequences of interaction of the Bcl-2 family with membranes. Apoptosis, 12(5), 897-911. doi:10.1007/s10495-007-0746-4
Levin, B., & Amos, C. (1995). Therapy of unresectable hepatocellular carcinoma. N Engl J Med, 332(19), 1294-1296. doi:10.1056/nejm199505113321910
Levitzki, A. (1992). Tyrphostins: tyrosine kinase blockers as novel antiproliferative agents and dissectors of signal transduction. Faseb j, 6(14), 3275-3282. doi:10.1096/fasebj.6.14.1426765
Li, L., Li, J. C., Yang, H., Zhang, X., Liu, L. L., Li, Y., . . . Guan, X. Y. (2018). Expansion of cancer stem cell pool initiates lung cancer recurrence before angiogenesis. Proc Natl Acad Sci U S A, 115(38), E8948-e8957. doi:10.1073/pnas.1806219115
Li, W., Katz, B. P., & Spinola, S. M. (2012). Haemophilus ducreyi-induced interleukin-10 promotes a mixed M1 and M2 activation program in human macrophages. Infect Immun, 80(12), 4426-4434. doi:10.1128/iai.00912-12
Li, X. F., Chen, C., Xiang, D. M., Qu, L., Sun, W., Lu, X. Y., . . . Ding, J. (2017). Chronic inflammation-elicited liver progenitor cell conversion to liver cancer stem cell with clinical significance. Hepatology, 66(6), 1934-1951. doi:10.1002/hep.29372
Liang, Y., Zheng, T., Song, R., Wang, J., Yin, D., Wang, L., . . . Liu, L. (2013). Hypoxia-mediated sorafenib resistance can be overcome by EF24 through Von Hippel-Lindau tumor suppressor-dependent HIF-1α inhibition in hepatocellular carcinoma. Hepatology, 57(5), 1847-1857. doi:https://doi.org/10.1002/hep.26224
Lin, S., Hoffmann, K., & Schemmer, P. (2012). Treatment of hepatocellular carcinoma: a systematic review. Liver cancer, 1(3-4), 144-158. doi:10.1159/000343828
Lin, S., Hoffmann, K., & Schemmer, P. (2012). Treatment of hepatocellular carcinoma: a systematic review. Liver cancer, 1(3-4), 144-158. doi:10.1159/000343828
Liu, C. P., Zhang, X., Tan, Q. L., Xu, W. X., Zhou, C. Y., Luo, M., . . . Zeng, X. (2017). NF-κB pathways are involved in M1 polarization of RAW 264.7 macrophage by polyporus polysaccharide in the tumor microenvironment. PLoS ONE, 12(11), e0188317. doi:10.1371/journal.pone.0188317
Llovet, J. M., & Bruix, J. (2003). Systematic review of randomized trials for unresectable hepatocellular carcinoma: Chemoembolization improves survival. Hepatology, 37(2), 429-442. doi:10.1053/jhep.2003.50047
Llovet, J. M., Ricci, S., Mazzaferro, V., Hilgard, P., Gane, E., Blanc, J.-F., . . . Bruix, J. (2008). Sorafenib in Advanced Hepatocellular Carcinoma. New England Journal of Medicine, 359(4), 378-390. doi:10.1056/NEJMoa0708857
Llovet, J. M., Zucman-Rossi, J., Pikarsky, E., Sangro, B., Schwartz, M., Sherman, M., & Gores, G. (2016). Hepatocellular carcinoma. Nat Rev Dis Primers, 2, 16018. doi:10.1038/nrdp.2016.18
Lytle, N. K., Barber, A. G., & Reya, T. (2018). Stem cell fate in cancer growth, progression and therapy resistance. Nature Reviews Cancer, 18(11), 669-680. doi:10.1038/s41568-018-0056-x
Ma, S., Lee, T. K., Zheng, B. J., Chan, K. W., & Guan, X. Y. (2008). CD133+ HCC cancer stem cells confer chemoresistance by preferential expression of the Akt/PKB survival pathway. Oncogene, 27(12), 1749-1758. doi:10.1038/sj.onc.1210811
Mantovani, A., Sozzani, S., Locati, M., Allavena, P., & Sica, A. (2002). Macrophage polarization: tumor-associated macrophages as a paradigm for polarized M2 mononuclear phagocytes. Trends in Immunology, 23(11), 549-555. doi:https://doi.org/10.1016/S1471-4906(02)02302-5
Martinez, F. O., & Gordon, S. (2014). The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep, 6, 13. doi:10.12703/p6-13
Meads, M. B., Gatenby, R. A., & Dalton, W. S. (2009). Environment-mediated drug resistance: a major contributor to minimal residual disease. Nature Reviews Cancer, 9(9), 665-674. doi:10.1038/nrc2714
Meads, M. B., Hazlehurst, L. A., & Dalton, W. S. (2008). The Bone Marrow Microenvironment as a Tumor Sanctuary and Contributor to Drug Resistance. Clinical Cancer Research, 14(9), 2519-2526. doi:10.1158/1078-0432.ccr-07-2223
Mittal, D., Gubin, M. M., Schreiber, R. D., & Smyth, M. J. (2014). New insights into cancer immunoediting and its three component phases--elimination, equilibrium and escape. Curr Opin Immunol, 27, 16-25. doi:10.1016/j.coi.2014.01.004
Miyake, M., Hori, S., Morizawa, Y., Tatsumi, Y., Nakai, Y., Anai, S., . . . Fujimoto, K. (2016). CXCL1-Mediated Interaction of Cancer Cells with Tumor-Associated Macrophages and Cancer-Associated Fibroblasts Promotes Tumor Progression in Human Bladder Cancer. Neoplasia, 18(10), 636-646. doi:10.1016/j.neo.2016.08.002
Mollica Poeta, V., Massara, M., Capucetti, A., & Bonecchi, R. (2019). Chemokines and Chemokine Receptors: New Targets for Cancer Immunotherapy. Frontiers in Immunology, 10(379). doi:10.3389/fimmu.2019.00379
Moreau, K., Luo, S., & Rubinsztein, D. (2010). Cytoprotective roles for autophagy. Current opinion in cell biology, 22, 206-211. doi:10.1016/j.ceb.2009.12.002
Mukherjee, N., Schwan, J. V., Fujita, M., Norris, D. A., & Shellman, Y. G. (2015). Alternative Treatments For Melanoma: Targeting BCL-2 Family Members to De-Bulk and Kill Cancer Stem Cells. Journal of Investigative Dermatology, 135(9), 2155-2161. doi:https://doi.org/10.1038/jid.2015.145
Murray, P. J. (2017). Macrophage Polarization. Annu Rev Physiol, 79, 541-566. doi:10.1146/annurev-physiol-022516-034339
Murray, P. J., & Wynn, T. A. (2011). Protective and pathogenic functions of macrophage subsets. Nat Rev Immunol, 11(11), 723-737. doi:10.1038/nri3073
Niu, L., Liu, L., Yang, S., Ren, J., Lai, P. B. S., & Chen, G. G. (2017). New insights into sorafenib resistance in hepatocellular carcinoma: Responsible mechanisms and promising strategies. Biochim Biophys Acta Rev Cancer, 1868(2), 564-570. doi:10.1016/j.bbcan.2017.10.002
Novak, M. L., & Koh, T. J. (2013). Macrophage phenotypes during tissue repair. J Leukoc Biol, 93(6), 875-881. doi:10.1189/jlb.1012512
Novo, E., Cannito, S., Zamara, E., Valfrè di Bonzo, L., Caligiuri, A., Cravanzola, C., . . . Parola, M. (2007). Proangiogenic cytokines as hypoxia-dependent factors stimulating migration of human hepatic stellate cells. Am J Pathol, 170(6), 1942-1953. doi:10.2353/ajpath.2007.060887
Osherov, N., Gazit, A., Gilon, C., & Levitzki, A. (1993). Selective inhibition of the epidermal growth factor and HER2/neu receptors by tyrphostins. J Biol Chem, 268(15), 11134-11142.
Padma, V. V. (2015). An overview of targeted cancer therapy. Biomedicine (Taipei), 5(4), 19. doi:10.7603/s40681-015-0019-4
Park, C. Y., Tseng, D., & Weissman, I. L. (2009). Cancer stem cell-directed therapies: recent data from the laboratory and clinic. Mol Ther, 17(2), 219-230. doi:10.1038/mt.2008.254
Park, E., Chen, J., Moore, A., Mangolini, M., Santoro, A., Boyd, J. R., . . . Ringshausen, I. (2020). Stromal cell protein kinase C-β inhibition enhances chemosensitivity in B cell malignancies and overcomes drug resistance. Sci Transl Med, 12(526). doi:10.1126/scitranslmed.aax9340
Pinato, D. J., Guerra, N., Fessas, P., Murphy, R., Mineo, T., Mauri, F. A., . . . Rimassa, L. (2020). Immune-based therapies for hepatocellular carcinoma. Oncogene, 39(18), 3620-3637. doi:10.1038/s41388-020-1249-9
Polier, S., Samant, R. S., Clarke, P. A., Workman, P., Prodromou, C., & Pearl, L. H. (2013). ATP-competitive inhibitors block protein kinase recruitment to the Hsp90-Cdc37 system. Nat Chem Biol, 9(5), 307-312. doi:10.1038/nchembio.1212
Porta, C., Riboldi, E., Ippolito, A., & Sica, A. (2015). Molecular and epigenetic basis of macrophage polarized activation. Seminars in Immunology, 27(4), 237-248. doi:https://doi.org/10.1016/j.smim.2015.10.003
Posner, I., Engel, M., Gazit, A., & Levitzki, A. (1994). Kinetics of inhibition by tyrphostins of the tyrosine kinase activity of the epidermal growth factor receptor and analysis by a new computer program. Mol Pharmacol, 45(4), 673-683.
The Power and the Promise of Liver Cancer Stem Cell Markers. (2011). Stem Cells and Development, 20(12), 2023-2030. doi:10.1089/scd.2011.0012
Prager, B. C., Xie, Q., Bao, S., & Rich, J. N. (2019). Cancer Stem Cells: The Architects of the Tumor Ecosystem. Cell Stem Cell, 24(1), 41-53. doi:10.1016/j.stem.2018.12.009
Qiu, Y., Shan, W., Yang, Y., Jin, M., Dai, Y., Yang, H., . . . Li, Y. (2019). Reversal of sorafenib resistance in hepatocellular carcinoma: epigenetically regulated disruption of 14-3-3η/hypoxia-inducible factor-1α. Cell Death Discovery, 5(1), 120. doi:10.1038/s41420-019-0200-8
Raza, A., & Sood, G. K. (2014). Hepatocellular carcinoma review: current treatment, and evidence-based medicine. World journal of gastroenterology, 20(15), 4115-4127. doi:10.3748/wjg.v20.i15.4115
Reya, T., Morrison, S. J., Clarke, M. F., & Weissman, I. L. (2001). Stem cells, cancer, and cancer stem cells. Nature, 414(6859), 105-111. doi:10.1038/35102167
Rimassa, L. (2018). Drugs in Development for Hepatocellular Carcinoma. Gastroenterology & hepatology, 14(9), 542-544.
Ringe, B., Pichlmayr, R., Wittekind, C., & Tusch, G. (1991). Surgical treatment of hepatocellular carcinoma: experience with liver resection and transplantation in 198 patients. World J Surg, 15(2), 270-285. doi:10.1007/bf01659064
Rosmorduc, O., Wendum, D., Corpechot, C., Galy, B., Sebbagh, N., Raleigh, J., . . . Poupon, R. (1999). Hepatocellular hypoxia-induced vascular endothelial growth factor expression and angiogenesis in experimental biliary cirrhosis. Am J Pathol, 155(4), 1065-1073. doi:10.1016/s0002-9440(10)65209-1
Rőszer, T. (2015). Understanding the Mysterious M2 Macrophage through Activation Markers and Effector Mechanisms. Mediators of Inflammation, 2015, 816460. doi:10.1155/2015/816460
Saigusa, S., Tanaka, K., Toiyama, Y., Yokoe, T., Okugawa, Y., Ioue, Y., . . . Kusunoki, M. (2009). Correlation of CD133, OCT4, and SOX2 in rectal cancer and their association with distant recurrence after chemoradiotherapy. Ann Surg Oncol, 16(12), 3488-3498. doi:10.1245/s10434-009-0617-z
Samarin, J., Laketa, V., Malz, M., Roessler, S., Stein, I., Horwitz, E., . . . Breuhahn, K. (2016). PI3K/AKT/mTOR-dependent stabilization of oncogenic far-upstream element binding proteins in hepatocellular carcinoma cells. Hepatology, 63(3), 813-826. doi:10.1002/hep.28357
Sarasin, F. P., Majno, P. E., Llovet, J. M., Bruix, J., Mentha, G., & Hadengue, A. (2001). Living donor liver transplantation for early hepatocellular carcinoma: A life-expectancy and cost-effectiveness perspective. Hepatology, 33(5), 1073-1079. doi:10.1053/jhep.2001.23311
Sarveazad, A., Agah, S., Babahajian, A., Amini, N., & Bahardoust, M. (2019). Predictors of 5 year survival rate in hepatocellular carcinoma patients. Journal of research in medical sciences : the official journal of Isfahan University of Medical Sciences, 24, 86-86. doi:10.4103/jrms.JRMS_1017_18
Satoh, T., Takeuchi, O., Vandenbon, A., Yasuda, K., Tanaka, Y., Kumagai, Y., . . . Akira, S. (2010). The Jmjd3-Irf4 axis regulates M2 macrophage polarization and host responses against helminth infection. Nature Immunology, 11(10), 936-944. doi:10.1038/ni.1920
Siegel, R., Naishadham, D., & Jemal, A. (2013). Cancer statistics, 2013. CA Cancer J Clin, 63(1), 11-30. doi:10.3322/caac.21166
Siegel, R. L., Miller, K. D., & Jemal, A. (2020). Cancer statistics, 2020. CA: A Cancer Journal for Clinicians, 70(1), 7-30. doi:10.3322/caac.21590
Song, K. A., & Faber, A. C. (2019). Epithelial-to-mesenchymal transition and drug resistance: transitioning away from death. J Thorac Dis, 11(6), E82-e85. doi:10.21037/jtd.2019.06.11
Song, K. D. (2016). Percutaneous cryoablation for hepatocellular carcinoma. Clinical and molecular hepatology, 22(4), 509-515. doi:10.3350/cmh.2016.0079
Song, K. D. (2016). Percutaneous cryoablation for hepatocellular carcinoma. Clinical and molecular hepatology, 22(4), 509-515. doi:10.3350/cmh.2016.0079
Song, M. J. (2015). Hepatic artery infusion chemotherapy for advanced hepatocellular carcinoma. World journal of gastroenterology, 21(13), 3843-3849. doi:10.3748/wjg.v21.i13.3843
Stein, M., Keshav, S., Harris, N., & Gordon, S. (1992). Interleukin 4 potently enhances murine macrophage mannose receptor activity: a marker of alternative immunologic macrophage activation. J Exp Med, 176(1), 287-292. doi:10.1084/jem.176.1.287
Steinbichler, T. B., Savic, D., Dudás, J., Kvitsaridze, I., Skvortsov, S., Riechelmann, H., & Skvortsova, I.-I. (2020). Cancer stem cells and their unique role in metastatic spread. Seminars in cancer biology, 60, 148-156. doi:10.1016/j.semcancer.2019.09.007
Straub, A. C., Stolz, D. B., Ross, M. A., Hernández-Zavala, A., Soucy, N. V., Klei, L. R., & Barchowsky, A. (2007). Arsenic stimulates sinusoidal endothelial cell capillarization and vessel remodeling in mouse liver. Hepatology, 45(1), 205-212. doi:10.1002/hep.21444
Sui, Y., Zheng, X., & Zhao, D. (2015). Rab31 promoted hepatocellular carcinoma (HCC) progression via inhibition of cell apoptosis induced by PI3K/AKT/Bcl-2/BAX pathway. Tumour Biol, 36(11), 8661-8670. doi:10.1007/s13277-015-3626-5
Sun, C., Sun, L., Jiang, K., Gao, D.-M., Kang, X.-N., Wang, C., . . . Liu, Y.-K. (2013). NANOG promotes liver cancer cell invasion by inducing epithelial–mesenchymal transition through NODAL/SMAD3 signaling pathway. Int J Biochem Cell Biol, 45(6), 1099-1108. doi:https://doi.org/10.1016/j.biocel.2013.02.017
Sun, C., Sun, L., Jiang, K., Gao, D. M., Kang, X. N., Wang, C., . . . Liu, Y. K. (2013). NANOG promotes liver cancer cell invasion by inducing epithelial-mesenchymal transition through NODAL/SMAD3 signaling pathway. Int J Biochem Cell Biol, 45(6), 1099-1108. doi:10.1016/j.biocel.2013.02.017
Tang, W., Chen, Z., Zhang, W., Cheng, Y., Zhang, B., Wu, F., . . . Wang, X. (2020). The mechanisms of sorafenib resistance in hepatocellular carcinoma: theoretical basis and therapeutic aspects. Signal Transduction and Targeted Therapy, 5(1), 87. doi:10.1038/s41392-020-0187-x
Thiery, J. P. (2003). Epithelial–mesenchymal transitions in development and pathologies. Current opinion in cell biology, 15(6), 740-746. doi:https://doi.org/10.1016/j.ceb.2003.10.006
Thiery, J. P., & Sleeman, J. P. (2006). Complex networks orchestrate epithelial–mesenchymal transitions. Nature Reviews Molecular Cell Biology, 7(2), 131-142. doi:10.1038/nrm1835
Tijeras-Raballand, A., Hainaud-Hakim, P., Contreres, J. O., Gest, C., Le Henaff, C., Levy, B. I., . . . Dupuy, E. (2010). Rosuvastatin counteracts vessel arterialisation and sinusoid capillarisation, reduces tumour growth, and prolongs survival in murine hepatocellular carcinoma. Gastroenterol Res Pract, 2010, 640797. doi:10.1155/2010/640797
Trisciuoglio, D., Tupone, M. G., Desideri, M., Di Martile, M., Gabellini, C., Buglioni, S., . . . Del Bufalo, D. (2017). BCL-XL overexpression promotes tumor progression-associated properties. Cell Death & Disease, 8(12), 3216. doi:10.1038/s41419-017-0055-y
Tsuji, T., Ibaragi, S., & Hu, G. F. (2009). Epithelial-mesenchymal transition and cell cooperativity in metastasis. Cancer Res, 69(18), 7135-7139. doi:10.1158/0008-5472.can-09-1618
Tunissiolli, N. M., Castanhole-Nunes, M. M. U., Pavarino, É. C., da Silva, R. F., da Silva, R. d. C. M. A., & Maria Goloni-Bertollo, E. (2018). Clinical, Epidemiological and Histopathological Aspects in Patients with Hepatocellular Carcinoma Undergoing Liver Transplantation. Asian Pacific journal of cancer prevention : APJCP, 19(10), 2795-2802. doi:10.22034/APJCP.2018.19.10.2795
Vinogradov, S., & Wei, X. (2012). Cancer stem cells and drug resistance: the potential of nanomedicine. Nanomedicine (Lond), 7(4), 597-615. doi:10.2217/nnm.12.22
Waibel, M., Solomon, V. S., Knight, D. A., Ralli, R. A., Kim, S. K., Banks, K. M., . . . Johnstone, R. W. (2013). Combined targeting of JAK2 and Bcl-2/Bcl-xL to cure mutant JAK2-driven malignancies and overcome acquired resistance to JAK2 inhibitors. Cell Rep, 5(4), 1047-1059. doi:10.1016/j.celrep.2013.10.038
Wan, S., Zhao, E., Kryczek, I., Vatan, L., Sadovskaya, A., Ludema, G., . . . Welling, T. H. (2014). Tumor-associated macrophages produce interleukin 6 and signal via STAT3 to promote expansion of human hepatocellular carcinoma stem cells. Gastroenterology, 147(6), 1393-1404. doi:10.1053/j.gastro.2014.08.039
Wang, L. X., Zhang, S. X., Wu, H. J., Rong, X. L., & Guo, J. (2019). M2b macrophage polarization and its roles in diseases. J Leukoc Biol, 106(2), 345-358. doi:10.1002/jlb.3ru1018-378rr
Wang, N., Liang, H., & Zen, K. (2014). Molecular mechanisms that influence the macrophage m1-m2 polarization balance. Front Immunol, 5, 614. doi:10.3389/fimmu.2014.00614
Wang, Y., Tu, L., Du, C., Xie, X., Liu, Y., Wang, J., . . . Luo, F. (2018). CXCR2 is a novel cancer stem-like cell marker for triple-negative breast cancer. Onco Targets Ther, 11, 5559-5567. doi:10.2147/ott.s174329
Weishaupt, N., Blesch, A., & Fouad, K. (2012). BDNF: the career of a multifaceted neurotrophin in spinal cord injury. Exp Neurol, 238(2), 254-264. doi:10.1016/j.expneurol.2012.09.001
Weisser, S. B., McLarren, K. W., Kuroda, E., & Sly, L. M. (2013). Generation and characterization of murine alternatively activated macrophages. Methods Mol Biol, 946, 225-239. doi:10.1007/978-1-62703-128-8_14
West, H., & Jin, J. O. (2015). Transarterial Chemoembolization. JAMA Oncology, 1(8), 1178-1178. doi:10.1001/jamaoncol.2015.3702
Wheeler, M. D. (2003). Endotoxin and Kupffer cell activation in alcoholic liver disease. Alcohol Res Health, 27(4), 300-306.
Wishart, D. S., Knox, C., Guo, A. C., Shrivastava, S., Hassanali, M., Stothard, P., . . . Woolsey, J. (2006). DrugBank: a comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res, 34(Database issue), D668-672. doi:10.1093/nar/gkj067
Xu, G., & McLeod, H. L. (2001). Strategies for Enzyme/Prodrug Cancer Therapy. Clinical Cancer Research, 7(11), 3314-3324.
Xue, X., Liao, W., & Xing, Y. (2020). Comparison of clinical features and outcomes between HBV-related and non-B non-C hepatocellular carcinoma. Infectious Agents and Cancer, 15(1), 11. doi:10.1186/s13027-020-0273-2
Yaish, P., Gazit, A., Gilon, C., & Levitzki, A. (1988). Blocking of EGF-dependent cell proliferation by EGF receptor kinase inhibitors. Science, 242(4880), 933-935. doi:10.1126/science.3263702
Yang, J. D., Hainaut, P., Gores, G. J., Amadou, A., Plymoth, A., & Roberts, L. R. (2019). A global view of hepatocellular carcinoma: trends, risk, prevention and management. Nat Rev Gastroenterol Hepatol, 16(10), 589-604. doi:10.1038/s41575-019-0186-y
Yang, Z. F., & Poon, R. T. (2008). Vascular changes in hepatocellular carcinoma. Anat Rec (Hoboken), 291(6), 721-734. doi:10.1002/ar.20668
Yang, Z. F., & Poon, R. T. P. (2008). Vascular Changes in Hepatocellular Carcinoma. The Anatomical Record, 291(6), 721-734. doi:https://doi.org/10.1002/ar.20668
Yao, W., Ba, Q., Li, X., Li, H., Zhang, S., Yuan, Y., . . . Wang, H. (2017). A Natural CCR2 Antagonist Relieves Tumor-associated Macrophage-mediated Immunosuppression to Produce a Therapeutic Effect for Liver Cancer. EBioMedicine, 22, 58-67. doi:10.1016/j.ebiom.2017.07.014
Yao, Y., Xu, X.-H., & Jin, L. (2019). Macrophage Polarization in Physiological and Pathological Pregnancy. Frontiers in Immunology, 10, 792-792. doi:10.3389/fimmu.2019.00792
Yao, Y., Xu, X. H., & Jin, L. (2019). Macrophage Polarization in Physiological and Pathological Pregnancy. Front Immunol, 10, 792. doi:10.3389/fimmu.2019.00792
Yau, T., Park, J., Finn, R., Cheng, A. L., Mathurin, P., Edeline, J., . . . Sangro, B. (2019). LBA38_PRCheckMate 459: A randomized, multi-center phase III study of nivolumab (NIVO) vs sorafenib (SOR) as first-line (1L) treatment in patients (pts) with advanced hepatocellular carcinoma (aHCC). Annals of Oncology, 30. doi:10.1093/annonc/mdz394.029
Yochum, Z. A., Cades, J., Wang, H., Chatterjee, S., Simons, B. W., O'Brien, J. P., . . . Burns, T. F. (2019). Targeting the EMT transcription factor TWIST1 overcomes resistance to EGFR inhibitors in EGFR-mutant non-small-cell lung cancer. Oncogene, 38(5), 656-670. doi:10.1038/s41388-018-0482-y
Yoshiji, H., Kuriyama, S., Yoshii, J., Ikenaka, Y., Noguchi, R., Hicklin, D. J., . . . Fukui, H. (2003). Vascular endothelial growth factor and receptor interaction is a prerequisite for murine hepatic fibrogenesis. Gut, 52(9), 1347-1354. doi:10.1136/gut.52.9.1347
Youle, R. J., & Strasser, A. (2008). The BCL-2 protein family: opposing activities that mediate cell death. Nat Rev Mol Cell Biol, 9(1), 47-59. doi:10.1038/nrm2308
Yu, T., Gan, S., Zhu, Q., Dai, D., Li, N., Wang, H., . . . Xiao, Y. (2019). Modulation of M2 macrophage polarization by the crosstalk between Stat6 and Trim24. Nature Communications, 10(1), 4353. doi:10.1038/s41467-019-12384-2
Zhai, B., Hu, F., Jiang, X., Xu, J., Zhao, D., Liu, B., . . . Sun, X. (2014). Inhibition of Akt reverses the acquired resistance to sorafenib by switching protective autophagy to autophagic cell death in hepatocellular carcinoma. Mol Cancer Ther, 13(6), 1589-1598. doi:10.1158/1535-7163.mct-13-1043
Zhang, J.-L., Gong, L.-Q., Yan, Q., Zhou, N.-N., Lee, V. H.-F., & Guan, X.-Y. (2019). Advances in surface markers of liver cancer stem cell. Hepatoma Research, 5, 27. doi:10.20517/2394-5079.2019.13
Zhou, M., Zhang, Q., Zhao, J., Liao, M., Wen, S., & Yang, M. (2017). Phosphorylation of Bcl-2 plays an important role in glycochenodeoxycholate-induced survival and chemoresistance in HCC. Oncol Rep, 38(3), 1742-1750. doi:10.3892/or.2017.5830
Zhou, S. L., Zhou, Z. J., Hu, Z. Q., Huang, X. W., Wang, Z., Chen, E. B., . . . Zhou, J. (2016). Tumor-Associated Neutrophils Recruit Macrophages and T-Regulatory Cells to Promote Progression of Hepatocellular Carcinoma and Resistance to Sorafenib. Gastroenterology, 150(7), 1646-1658.e1617. doi:10.1053/j.gastro.2016.02.040
Zhu, A. X., Duda, D. G., Sahani, D. V., & Jain, R. K. (2011). HCC and angiogenesis: possible targets and future directions. Nat Rev Clin Oncol, 8(5), 292-301. doi:10.1038/nrclinonc.2011.30
Zizzo, G., Hilliard, B. A., Monestier, M., & Cohen, P. L. (2012). Efficient clearance of early apoptotic cells by human macrophages requires M2c polarization and MerTK induction. J Immunol, 189(7), 3508-3520. doi:10.4049/jimmunol.1200662
Blachier, M., H. Leleu, M. Peck-Radosavljevic, D. C. Valla and F. Roudot-Thoraval (2013). "The burden of liver disease in Europe: a review of available epidemiological data." J Hepatol 58(3): 593-608.
Weishaupt, N., A. Blesch and K. Fouad (2012). "BDNF: the career of a multifaceted neurotrophin in spinal cord injury." Exp Neurol 238(2): 254-264.
Tunissiolli, N. M., M. M. U. Castanhole-Nunes, É. C. Pavarino, R. F. da Silva, R. d. C. M. A. da Silva and E. Maria Goloni-Bertollo (2018). "Clinical, Epidemiological and Histopathological Aspects in Patients with Hepatocellular Carcinoma Undergoing Liver Transplantation." Asian Pacific journal of cancer prevention : APJCP 19(10): 2795-2802.
Hellerbrand, C., A. Hartmann, G. Richter, A. Knöll, R. Wiest, J. Schölmerich and G. Lock (2001). "Hepatocellular Carcinoma in Southern Germany: Epidemiological and Clinicopathological Characteristics and Risk Factors." Digestive Diseases 19(4): 345-351.