**2. Background**

Cholangiocarcinoma arises from the neoplastic transformation of cholangiocytes and can exist as either intrahepatic, perihilar or distal extrahepatic tumors (Alpini et al. 2001). Typically, cholangiocarcinomas are adenocarcinomas and have a poor prognosis and limited treatment options. This is due, at least in part, to the late presentation of symptoms and the relative resistance to current treatment options (Sirica 2005).

The incidence of both intra- and extra-hepatic cholangiocarcinoma is typically more prevalent in Asian countries (Patel 2002). The mortality rates for intrahepatic cholangiocarcinoma have increased since the 1970s, whereas deaths from extrahepatic cholangiocarcinoma have declined in most countries (Patel 2002). There is a slight preponderance for cholangiocarcinoma in males (Tominaga and Kuroishi 1994) and the incidence in both sexes increases with age (Patel 2002).

### **2.1 Risk factors**

Cholangiocarcinoma occurs with varying frequency in different regions of the world. This can be explained in part by the distribution of risk factors in geographic regions and ethnic groups (Ben-Menachem 2007). The common link between these regional risk factors seems to involve chronic inflammation and biliary irritation (Gores 2003).

The prevalence of cholangiocarcinoma in Asian countries shares a relationship with infections such as liver flukes, Hepatitis B and Hepatitis C (Ben-Menachem 2007). In contrast, approximately 90% of patients diagnosed with cholangiocarcinoma in Western countries do not have any recognized risk factors (Ben-Menachem 2007). However, the remaining 10% of cases are associated with certain risk factors. Apart from factors related to chronic inflammation, both intra- and extrahepatic cholangiocarcinomas are well-known complications of primary sclerosing cholangitis (de Groen et al. 1999). Other known risk factors include obesity, hepatolithiasis, bacterial infection and/or bile stasis-related chronic cholangitis (Chen 1999; de Groen et al. 1999; Catalano et al. 2009).

## **3. Tumor microenvironment**

Neoplastic epithelial cells coexist with a biologically complex stroma composed of various types of stromal cells as well as the extracellular matrix, both of which create the complexity of the tumor microenvironment (Orimo and Weinberg 2006). Mouse models of tumorigenesis have revealed that stromal cells, in particular inflammatory cells, vascular endothelial cells and fibroblasts actively support tumor growth (Olumi et al. 1999; Tlsty 2001; Cunha et al. 2003; Bhowmick et al. 2004). In addition, the microenvironment is now well recognized as playing a role in neoplastic transformation, malignant progression and metastasis and invasion of cancer cells (Tlsty 2001; Bhowmick et al. 2004). Furthermore, the interaction between the cancer cells and the tumor microenvironment is a major factor influencing cancer treatment resistance to radiotherapy and chemotherapy (de Visser and Jonkers 2009; Shinohara and Maity 2009). Research indicates that the interplay between the cancer cells and the stromal cells of the microenvironment is bi-directional and dynamic. For example, neoplastic cells often secrete factors that work in a paracrine manner to recruit and activate a number of types of stromal cells into the tumor microenvironment as required (Rasanen and Vaheri 2010; Rojas et al. 2010; Onimaru and Yonemitsu 2011). Conversely, stromal cells, once recruited and activated, release factors into the extracellular milieu that can either stimulate or inhibit growth of the tumor (Rasanen and Vaheri 2010; Rojas et al. 2010; Onimaru and Yonemitsu 2011). The effects of the components of the tumor microenvironment on tumor growth are summarized in Figure 1. In particular, the proliferation and recruitment of vascular endothelial cells and subsequent formation of new blood vessels brings a nutrient supply thereby allowing growth and metastasis of the tumor. Cancer associated fibroblasts, on the other hand, can stimulate angiogenesis as well promote tumor growth and invasion. The presence of immune cells, in particular tumor-associated macrophages, in the microenvironment, confers resistance to toxic insults and also promotes growth. Lastly, proliferation of lymph endothelial cells and subsequent increase in lymphatic vessel density promotes tumor metastasis.

Fig. 1. Schematic representation of the effects of stromal support cells on tumor growth and metastasis. Abbreviations: B, B cell; BV, Blood vessel; EMT, Epithelial-mesenchymal transition; LV, lymph vessel; M, monocyte; T, T cell; TAM, Tumor associated macrophage.
