Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted

Abstract 2806: Inactivation of PBRM1, a gene frequently mutated in clear cell renal carcinoma, suppresses tumor growth

Abstract The genetics of renal cancer is dominated by inactivation of the VHL tumour suppressor gene in clear cell renal carcinoma (ccRCC), the commonest histological subtype. However, our previous work has demonstrated that VHL loss alone is insufficient for ccRCC tumourigenesis arguing the need for additional genetic events. Recently, we have sequenced of the protein coding exome in 257 cases of primary renal carcinoma (RCC) and reported the identification of the SWI/SNF chromatin remodeling complex gene Polybromo 1 (PBRM1) as a second major RCC cancer gene with truncating mutations in 41% (85/257) of cases. In particular, all 9 cases with a SETD2 mutation have a mutation in either PBRM1 or VHL, with 7 of 9 cases having mutations in all three genes. The concomitant VHL, PBRM1 and SETD2 mutations, with all three genes mapping to chromosome 3p, suggest that the mutations are non-redundant functionally. To obtain further evidence that PBRM1 can act as a cancer gene, transcriptional profiling before and after PBRM1 knockdown was performed using gene expression microarrays. The results showed that PBRM1 activity regulates pathways associated with chromosomal instability and cellular proliferation. Consistently, knockdown of PBRM1 RNA resulted in a significant increase in proliferation 4/5 RCC lines. No effect was seen, however, in A704 cell, which carries a homozygous truncating PBRM1 mutation, confirming the specificity of the assay. Further, knockdown of PBRM1 resulted in significantly increased colony formation in soft-agar and increased cell migration indicative of an increase in transformed phenotype. Taken together, these data support PBRM1 having a tumor suppressor role in ccRCC. Therefore, understanding the contribution of PBRM1 mutation to clinical disease progression and outcome as well the potential for exploiting SWI/SNF complex abrogation therapeutically are important future areas of renal cancer research. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2011-2806</jats:p

The Tumor Microenvironment and Immune Milieu of Cholangiocarcinoma

Tumor microenvironment is a complex, multicellular functional compartment that, particularly when assembled as an abundant desmoplastic reaction, may profoundly affect the proliferative and invasive abilities of epithelial cancer cells. Tumor microenvironment comprises not only stromal cells, mainly cancer-associated fibroblasts, but also immune cells of both the innate and adaptive system (tumor-associated macrophages, neutrophils, natural killer cells, and T and B lymphocytes), and endothelial cells. This results in an intricate web of mutual communications regulated by an extensively remodeled extracellular matrix, where the tumor cells are centrally engaged. In this regard, cholangiocarcinoma, in particular the intrahepatic variant, has become the focus of mounting interest in the last years, largely due to the lack of effective therapies despite its rising incidence and high mortality rates worldwide. On the other hand, recent studies in pancreatic cancer, which similarly to cholangiocarcinoma, is highly desmoplastic, have argued against a tumor-promoting function of the tumor microenvironment. In this review, we will discuss recent developments concerning the role of each cellular population and their multifaceted interplay with the malignant biliary epithelial counterpart. We ultimately hope to provide the working knowledge on how their manipulation may lead to a therapeutic gain in cholangiocarcinoma. This article is protected by copyright. All rights reserved