Disrpy may improve the treatment of liver cancer. Disruption of Microenvironment Hypoxia has been identified as a major cause of hypervascularization in HCC, and in patients with HCC, disease free survival is shorter when tumors express high levels of hypoxia inducible factor 1?? AP24534 Ponatinib Hypoxia influences microenvironment in HCC and liver CSCs. Induction of tumor hypoxia combined with chemotherapy by transcath eter transarterial chemoembolization has been widely used in treating unresectable HCC, but tumor re sponse rate is unsatisfactory and only a subgroup of patients benefit from this treatment. HIF 1??may be responsible for in this failure, as suggested by experimental findings obtained in a rat model of primary liver cancer.
Therefore, hypoxia driven clonal selection CAL-101 of apoptosis resistant tumor cells, together with hypoxia induced MDR1 expression and angiogenesis, explain why hypoxic tumors are more resistance to conventional anticancer therapy. This justifies the current trials evaluating the use of an ti angiogenic therapy following HCC surgery. Several studies have established that tumor growth and inva sion in HCC are dependent on dysregulated angio genesis. There is, therefore, a strong ra tionale for targeting growth factors that drive angio genic process as a potential therapeutic strategy for the treatment of HCC. VEGF is a key angiogenic fac tor, and several agents that target VEGF or VEGFR are currently in development for the treatment of HCC. These agents include the tyrosine kinase inhibitors Vatalanib and Cediranib , and the monoclonal antibody Bevacizumab , and multikinase inhibitors Sorafenib , Sunitinib , Brivanib , and Linifanib .
In addition, ligands that bind to the EGFR, such as EGF, have a vital role in both tumor angiogenesis and proliferation, thought to be primar ily through activation of the RAF MEK ERK and PI3K AKT mTOR pathways. Because of their effi cacy in other solid tumors and the integral role of growth factors in HCC development and progression, it was hypothesized that agents specifically targeting EGF EGFR signaling may also be beneficial in HCC. These agents include the tyrosine kinase inhibitors Erotinib, Lapatinib and Gefitinib Iressa, Astrazeneca Pharma ceuticals LP, Wilmington DE, USA, and the monoclonal antibody Cetuximab Er bitux, ImClone LLC, New York, NY, and Bris tol Myers Squibb, Princeton, NJ, USA.
Disruption of self protection Anti immune evasion The observation that tumors progress in patients with HCC despite the presence of tumor specific immune responses suggests that development of HCC leads to a number of immunosuppressive mechanism, which are important to be considered when designing immunotherapy protocols. These mechanisms include production of immunosuppres sive cytokines such as TGF ??and prostaglandins, impaired antigen presenting cells, generation of in hibitory macrophages, increase in regulatory T cells and induction of myeloid derived suppressor cells. All these factors provide an environ