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Briz et al. Liver cancer chemoresistance

human melanoma cells and increased sensitivity to cells that eventually enter into further steps of the
cytotoxic drugs in chemoresistant cell lines. [12] invasion-metastasis process.

Several strategies are currently being developed In liver cancer, a relationship between enhanced
to overcome tumor chemoresistance associated chemoresistance and EMT has also been recently
to microenvironment acidity including inhibition of described. [17] Poor differentiated liver cancer cell lines,
deprotonation mechanisms using drugs such as such as HLE, HLF and SK-Hep1, expressing high
inhibitors of proton transporters NHE-1, carbonic levels of mesenchymal markers were more invasive
anhydrases, monocarboxylate transporters and and resistant to cisplatin, doxorubicin and sorafenib
proton pumps (PPI). [13,14] A multicentre historically than other well-differentiated liver cancer cells, such
controlled trial has been performed to evaluate the as Hep3B, HepG2 and Huh7. It has been suggested
activity of a pre-treatment administration of the PPI that the development of a more invasive capability and
esomeprazole as chemosensitizer during neoadjuvant chemoresistance in tumor cells could be attributed
chemotherapy based on methotrexate, cisplatin and to EMT. Clinical observations support the concept
adriamycin in patients with osteosarcoma. [15] The that poorer differentiated HCC are more refractory to
analysis of the resected tumors after neoadjuvant chemotherapy based on inhibitors of receptors with
therapy revealed that pretreatment with the PPI tyrosine kinase activity (TKI). [18] Moreover, patients
increases the effectiveness of the polychemotherapy with undifferentiated tumors have a worse prognosis. [17]
at the tumor level. This was particularly evident in the
histological chondroblastic subtype which normally Although signals triggering EMT in carcinoma cells
shows poor histological response. This study provides are not well known, different signaling pathways have
evidences that PPI may be beneficially added to been involved in this process.
standard regimens in combination to conventional
chemotherapy. Other strategies involves the use of (1) Transforming growth factor-beta (TGF-b) signaling
induced tumor acidity as an attractant for antitumor pathway. TGF-b has been suggested to play an important
[19]
drugs such as cyclooxygenase inhibitors and role in promoting EMT in liver tumor cells. In a study
photoactivatable cytotoxic agents such as acridine carried out with gemcitabine-resistant MzChA-1 cells
orange and imidazoacridinones, with tropism for acid from human biliary tract cancer, a relationship between
environments, where they are activated. [13,14] an increase in TGF-β expression, EMT and enhanced
invasive activity was found. [20] SMAD proteins are
CHEMORESISTANCE DUE TO PHENOTYPE intracellular proteins belonging to the TFG-β pathway.
TRANSITION OF TUMOR CELLS (MOC-7) It has been demonstrated that down-regulation
of microRNA-145 (miR-145) in human HPB and
The epithelial-mesenchymal transition (EMT) is HCC cells, such as HepG2 and HuH7, respectively,
a process by which epithelial cells lose cell-cell increases resistance to doxorubicin through
interactions and polarity, and acquire a phenotype with enhancement of SMAD3 expression. [21] A relationship
mesenchymal characteristics, i.e. enhanced migratory between overexpression of SMAD2 and SMAD4 and
behavior, invasive ability, and resistance to apoptosis enhanced EMT resulting in mesenchymal phenotype
activation. Under physiological circumstances and reduced sensitivity to sorafenib and doxorubicin
during intrauterine life, EMT occurs transiently has been found both in vitro and in HCC patients. [22]
during embryogenesis and organ development, and A down-regulation of miR-125b, a microRNA whose
after birth in association with wound healing, tissue expression is strongly suppressed in HCC, has
regeneration and organ fibrogenesis in the context of been suggested to be involved in the acquisition of
normal morphogenesis. EMT also takes place in some chemoresistance in this type of tumor cells.
types of cancer, including HCC and CCA, in cells that
have previously undergone genetic changes affecting (2) Epidermal growth factor receptor (EGFR) signaling
oncogenes and/or tumor suppressor genes, which pathways. EMT status in HCC cells is also considered
favors carcinogenesis. [16] Carcinoma cells that have to be a determinant of sensitivity to EGFR inhibitors.
[23]
acquired a mesenchymal phenotype lose E-cadherin Amphiregulin, a ligand of the EGFR, which is not
expression and express mesenchymal markers, such expressed in healthy liver, is up-regulated during
as N-cadherin, alpha-smooth muscle actin (α-SMA), chronic liver injury, the background on which most
fibroblast-specific protein 1 (FSP1), vimentin, and liver tumors develop. Overexpression of amphiregulin
desmin. Commonly, carcinoma cells that have lost in SK-Hep1 cells enhanced their proliferation rate,
epithelial phenotype appear in the external layer of anchorage-independent growth, drug resistance, and
primary tumors and they are considered to be the in vivo tumorigenic potential. [24] Another signal able
24 Hepatoma Research ¦ Volume 3 ¦ January 19, 2017