Our finding of a lack of a survival difference between the S and S-CRT groups suggests that for patients with extrahepatic bile duct adenocarcinoma at high risk for locoregional recurrence (i.e., R1 resection or pN1 disease), adjuvant chemoradiation provides an equivalent overall survival despite of these worse prognostic features.

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In humans, connexins (Cxs) and pannexins (Panxs) are the building blocks of hemichannels. These proteins are frequently altered in neoplastic cells and have traditionally been considered as tumor suppressors. Alteration of Cxs and Panxs in cancer cells can be due to genetic, epigenetic and post-transcriptional/post-translational events. Activated hemichannels mediate the diffusional membrane transport of ions and small signaling molecules. In the last decade hemichannels have been shown to participate in diverse cell processes including the modulation of cell proliferation and survival. However, their possible role in tumor growth and expansion remains largely unexplored. Herein, we hypothesize about the possible role of hemichannels in carcinogenesis and tumor progression. To support this theory, we summarize the evidence regarding the involvement of hemichannels in cell proliferation and migration, as well as their possible role in the anti-tumor immune responses. In addition, we discuss the evidence linking hemichannels with cancer in diverse models and comment on the current technical limitations for their study.

IntroductionAnaplastic large-cell lymphoma (ALCL) 1 frequently carries the t(2;5)(p23;q35) 2 or other 2p23 locus rearrangements 3 that result in overexpression of anaplastic lymphoma kinase (ALK). The t(2;5), the most common abnormality, creates a novel fusion gene, npm-alk. Among other mechanisms, NPM-ALK is believed to mediate its oncogenic potential through activation of phosphatidylinositol 3-kinase (PI3K)/Akt and STAT3 signaling pathways resulting in downstream antiapoptotic signals. [4][5][6][7][8] The extrinsic apoptotic pathway is initiated by death surface receptors, a subgroup of the tumor necrosis factor receptor (TNFR) superfamily, that have a characteristic intracytoplasmic domain, designated the death domain (DD). Upon ligation, CD95 (FAS), the best characterized death surface receptor, oligomerizes at the cell membrane and recruits the adapter protein FADD (FAS-associated death domain protein) through DD-DD association. FADD, in turn, recruits procaspase-8 by its death effector domain (DED), initiating the formation of the death-inducing signaling complex (DISC). In the DISC, procaspase-8 molecules are located in close proximity and are autocatalytically processed to active caspase-8. In "type I" cells, death receptors induce strong caspase-8 activation, directly activating effector caspases, including caspase-3, to ensure apoptosis. In "type II" cells, low amounts of caspase-8 are activated, depending on a mitochondrial amplification mechanism through the cleavage of BID. 9,10 Death-receptor-induced apoptosis is inhibited by c-FLIP, a DED-containing protein with a nonfunctional caspaselike catalytic domain with antiapoptotic function in the DISC. 11,12 The death receptor system has been involved in normal and abnormal immune processes, 13,14 as well as in Hodgkin 15,16 and non-Hodgkin lymphomagenesis, 17 and it is currently attracting interest as a possible therapeutic target. 18,19 Here we show that overexpression of c-FLIP in ALCL may confer resistance to apoptosis induced by cell surface signals. Study design Cell linesTwo ALK ϩ (Karpas 299, SU-DHL1) 20 cell lines known to carry the t(2;5) were used. As controls, a CD30 ϩ T-cell lymphoma cell line, Mac2a (a gift from Dr K. Elenitoba-Johnson, Salt Lake City, UT), a Hodgkin lymphoma cell line, L-1236 (purchased from DSMZ, Braunschweig, Germany), and a mantle cell lymphoma cell line, Mino (a gift from Dr R. Ford, Houston, TX) were also used. The cell lines were maintained according to methods reported. 20 Karpas 299 and SU-DHL1 cells were treated with the PI3K inhibitor LY294002, and the JAK3 inhibitors, WHI-P131 and WHI-P154, at the indicated concentrations. Whole-cell lysates were prepared 24 or 48 hours following treatment. Karpas 299 and SU-DHL1 cells also were infected with the HA-tagged, constitutively active, myrAkt adenovirus 21 at a multiplicity of infection (MOI) of 20, previously shown to significantly increase Ser473 p-AKT levels in vitro (not shown). Induction and detection of apoptosisEach cell line (1 ϫ 10 6 cells/mL) was incubated...