Nicotine Promotes Tumor Growth and Metastasis in Mouse Models of Lung Cancer

Nicotine is the major addictive component of tobacco smoke. Although nicotine is generally thought to have limited ability to initiate cancer, it can induce cell proliferation and angiogenesis in a variety of systems. These properties might enable nicotine to facilitate the growth of tumors already initiated. Here we show that nicotine significantly promotes the progression and metastasis of tumors in mouse models of lung cancer. This effect was observed when nicotine was administered through intraperitoneal injections, or through over-the-counter transdermal patches.In the present study, Line1 mouse adenocarcinoma cells were implanted subcutaneously into syngenic BALB/c mice. Nicotine administration either by intraperitoneal (i.p.) injection or transdermal patches caused a remarkable increase in the size of implanted Line1 tumors. Once the tumors were surgically removed, nicotine treated mice had a markedly higher tumor recurrence (59.7%) as compared to the vehicle treated mice (19.5%). Nicotine also increased metastasis of dorsally implanted Line1 tumors to the lungs by 9 folds. These studies on transplanted tumors were extended to a mouse model where the tumors were induced by the tobacco carcinogen, NNK. Lung tumors were initiated in A/J mice by i.p. injection of NNK; administration of 1 mg/kg nicotine three times a week led to an increase in the size and the number of tumors formed in the lungs. In addition, nicotine significantly reduced the expression of epithelial markers, E-Cadherin and beta-Catenin as well as the tight junction protein ZO-1; these tumors also showed an increased expression of the alpha(7) nAChR subunit. We believe that exposure to nicotine either by tobacco smoke or nicotine supplements might facilitate increased tumor growth and metastasis.Our earlier results indicated that nicotine could induce invasion and epithelial-mesenchymal transition (EMT) in cultured lung, breast and pancreatic cancer cells. This study demonstrates for the first time that administration of nicotine either by i.p. injection or through over-the-counter dermal patches can promote tumor growth and metastasis in immunocompetent mice. These results suggest that while nicotine has only limited capacity to initiate tumor formation, it can facilitate the progression and metastasis of tumors pre-initiated by tobacco carcinogens

Gradient echo MRI of portal vein thrombosis.

The MR appearance of thrombosis of the portal vein and its branches using gradient echo (GRE) sequences is described. The study consists of two separate parts. In the first part, five normal volunteers were examined to select the optimal section plane for each portal vessel to be studied. Given the "time of flight" effect of GRE sequences, a scan plane perpendicular to the direction of flow was used to obtain maximal signal enhancement of flowing blood. In the second part of the study, 13 patients with thrombosis of the portal system diagnosed by Doppler sonography, CT, and digital subtraction angiography were examined with the GRE technique. Gradient echo MR confirmed the presence and defined the extent of vessel thrombosis with high diagnostic accuracy. In addition, it proved accurate in detecting portosystemic collaterals. We concluded that the GRE technique can be effectively used as a complement to conventional SE MR to further delineate portal vessels

Sonographic characterization of an accessory fissure of the left hepatic lobe determined by omental infolding.

This article describes the sonographic appearance of a very common accessory fissure of the liver located on the inferior side of the left lobe. The fissure was recognized in about 5\% of 800 consecutive subjects and showed variable appearance owing to different insertion levels on the inferior hepatic surface. It extended from the left hepatic border to the Rex's recess or alternatively to the falciform ligament or the gallbladder fossa and contained the hepatogastric and hepatoduodenal ligaments, as demonstrated by laparotomy in six cases. At surgery, there was no evidence of thickening of Glisson's capsule at the fissure site, thus suggesting that the fissure is the result of extrinsic remodeling of the left lobe by omental infolding

CD73 protein as a source of extracellular precursors for sustained NAD+ biosynthesis in FK866-treated tumor cells.

NAD(+) is mainly synthesized in human cells via the “salvage” pathways starting from nicotinamide, nicotinic acid, or nicotinamide riboside (NR). The inhibition with FK866 of the enzyme nicotinamide phosphoribosyltransferase (NAMPT), catalyzing the first reaction in the “salvage” pathway from nicotinamide, showed potent antitumor activity in several preclinical models of solid and hematologic cancers. In the clinical studies performed with FK866, however, no tumor remission was observed. Here we demonstrate that low micromolar concentrations of extracellular NAD(+) or NAD(+) precursors, nicotinamide mononucleotide (NMN) and NR, can reverse the FK866-induced cell death, this representing a plausible explanation for the failure of NAMPT inhibition as an anti-cancer therapy. NMN is a substrate of both ectoenzymes CD38 and CD73, with generation of NAM and NR, respectively. In this study, we investigated the roles of CD38 and CD73 in providing ectocellular NAD(+) precursors for NAD(+) biosynthesis and in modulating cell susceptibility to FK866. By specifically silencing or overexpressing CD38 and CD73, we demonstrated that endogenous CD73 enables, whereas CD38 impairs, the conversion of extracellular NMN to NR as a precursor for intracellular NAD(+) biosynthesis in human cells. Moreover, cell viability in FK866-treated cells supplemented with extracellular NMN was strongly reduced in tumor cells, upon pharmacological inhibition or specific down-regulation of CD73. Thus, our study suggests that genetic or pharmacologic interventions interfering with CD73 activity may prove useful to increase cancer cell sensitivity to NAMPT inhibitors