## 2 Classification of Cholangiocarcinoma
### MDR: Multidrug Resistance; MOC: Mechanisms of Chemoresistance  
Cholangiocarcinoma is characterized by a considerable resistance to the common chemotherapeutics and there is no treatment able to improve the prognosis. The use of chemotherapy is currently clearly indicated in the management of inoperable patients due to unresectable, metastatic disease, or recurrent CCA and it includes gemcitabine and cisplatin as the first line treatment [15]. The chemoresistance (MOC) is the result of synergistic mechanisms that make cancer cells refractory to cytostatic drugs [44; 45]. It is possible to schematize these different mechanisms: MOC-1 reduces drug uptake and enhances drug efflux; MOC-2 is involved in drug metabolism; MOC3 changes the drug targets; MOC-4 enhances DNA repair; MOC-5 decreases apoptosis and enhances survival; MOC-6 affects the tumor microenvironment; and MOC-7 enhances phenotype transition [40]. MOC \begin{table}
\begin{tabular}{c c c} \hline \hline \multicolumn{2}{c}{**Diagnostic Markers**} & \multicolumn{2}{c}{**P prognostic Markers**} \\ \hline \multicolumn{2}{c}{Endothelial marker (CD34)} & Vascular endothelium growth factor (VEGF) \\ \hline \multicolumn{2}{c}{Smooth muscle marker [32]} & Hypoxia-inducible transcription factors (HIF) \\ \hline \multicolumn{2}{c}{Cell surface heparin sulphate proteoglycan (GPC3)} & Endothelial specific markers (CD31, CD34 and VWF) \\ \hline \multirow{2}{*}{**HCC**} & Stress protein implicated in cell cycle progression, apoptosis and tumorigenesis (HSP70) & Matrix metalloproteinase (MMPs) \\ \hline \multicolumn{2}{c}{Catalysts of glutamine synthesis (GS)} & CDK inhibitors (p16, p18, p27 and p57) \\ \hline \multicolumn{2}{c}{Alpha-fetoprotein (AFP)} & Cell proliferation markers (Ki-67 and PCNA) \\ \hline \multicolumn{2}{c}{Zinc-dependent metallopeptidase (CD10)} & Tumor suppressor gene/protein (P53) \\ \hline \multicolumn{2}{c}{Carbohydrate 19-9 antigen (CA19-9)} & Epidermal growth factor receptor (EGFR) \\ \hline \multicolumn{2}{c}{Carcinoembryonic antigen (CEA)} & Cytokeratin-19 fragments in serum (CYFRA21-1) \\ \hline \multicolumn{2}{c}{Interleukin – 6 (IL-6)} \\ \hline \multicolumn{2}{c}{Cytokeratin-19 fragments in serum (CYFRA21-1)} \\ \hline \multicolumn{2}{c}{Matrix metallopeptidase 7 (MMP-7)} \\ \hline \multicolumn{2}{c}{Spermatogenesis associated 20 (SSP411 or SPATA20)} \\ \hline \multicolumn{2}{c}{Circulating tumor cells (CTC)} \\ \hline \hline \end{tabular}
\end{table} 
Table 1: List of the most important diagnostic biomarkers in Hepatocarcinoma (HCC) and Cholangiocarcinoma (CCA). characterizes the multidrug resistance (MDR) phenotype in CCA and is represented by the so-called _resistoma_, which in turn corresponds to the complete series of proteins associated with MOC and expressed in every moment of cancer evolution. MOCs result in reduced drug intake, increase in drug efflux, a lower percentage of intracellular active agent, and changes in molecular targets. MDR can be counteracted using gene therapy, pharmacological targeting, such as VEGF, which are secreted from tumors that up-regulate MDR through the activation of VEGFR and Akt. In fact, recent data indicate the inhibition of angiogenesis as an interesting therapeutic target against the tumor microenvironment [46]. Although data are still lacking and related aspects to the drug resistance mechanisms need to be clarified, effective anti-angiogenic therapy could be based on the identification of markers of reactivity or development, essential for an individual treatment. In addition, MDR can be also counteracted using nanotechnology to increase the absorption of conventional drugs [45].