Fatty Acid Synthase (FASN) and ATP-citrate lyase (ACLY), key enzymes of de novo lipogenesis, are significantly upregulated and activated in many cancers and portend poor prognosis. Even though the role of lipogenesis in providing proliferative and survival advantages to cancer cells has been described, the impact of aberrant activation of lipogenic enzymes on cancer progression remains unknown. In this study, we found that elevated expression of FASN is associated with advanced stages of colorectal cancer (CRC) and liver metastasis, suggesting that it may play a role in progression of CRC to metastatic disease. Targeted inhibition of lipogenic enzymes abolished expression of CD44, a transmembrane protein associated with metastases in several cancers including CRC. In addition, inhibition of lipogenic enzymes and reduced expression of CD44 attenuated the activation of MET, Akt, FAK, and paxillin, which are known to regulate adhesion, migration and invasion. These changes were consistent with an observed decrease in migration and adhesion of CRC cells in functional assays and with re-organization of actin cytoskeleton upon FASN inhibition. Despite the modest effect of FASN inhibition on tumor growth in xenografts, attenuation of lipogenesis completely abolished establishment of hepatic metastasis and formation of secondary metastasis. Together, our findings suggest that targeting de novo lipogenesis may be a potential treatment strategy for advanced CRC.

The review highlights the wide array of biological processes in which neurotensin has a role, and summarizes the most recent advances in various fields of neurotensin research. The knowledge gained through this research has led to the development of first-in-class drugs for the treatment of various medical conditions, and it is clear that in the coming years some of these agents will be ready to move from the bench to the bedside in clinical trials.

The majority of deaths from all cancers, including colorectal cancer (CRC), is a result of tumor metastasis to distant organs. To date, an effective and safe system capable of exclusively targeting metastatic cancers that have spread to distant organs or lymph nodes does not exist. Here, we constructed multifunctional RNA nanoparticles, derived from the three-way junction (3WJ) of bacteriophage phi29 motor pRNA, to target metastatic cancer cells in a clinically relevant mouse model of CRC metastasis. The RNA nanoparticles demonstrated metastatic tumor homing without accumulation in normal organ tissues surrounding metastatic tumors. The RNA nanoparticles simultaneously targeted CRC cancer cells in major sites of metastasis, such as liver, lymph nodes and lung. Our results demonstrate the therapeutic potential of these RNA nanoparticles as a delivery system for the treatment of CRC metastasis

Sound activates not only the cochlea but also the vestibular end organs. Research on this phenomenon led to the discovery of the sound-evoked vestibular myogenic potentials recorded from the sternocleidomastoid muscles (cervical VEMP, or cVEMP). Since the cVEMP offers simplicity and the ability to stimulate each labyrinth separately, its values as a test of human vestibular function are widely recognized. Currently, the cVEMP is interpreted as a test of saccule function based on the assumption that clicks primarily activate the saccule. However, sound activation of vestibular end organs other than the saccule has been reported. To provide the neural basis for interpreting clinical VEMP testing, we employed the broadband clicks used in clinical VEMP testing to examine the sound-evoked responses in a large sample of vestibular afferents in Sprague-Dawley rats. Recordings were made from 924 vestibular afferents from 106 rats: 255 from the anterior canal (AC), 202 from the horizontal canal (HC), 177 from the posterior canal (PC), 207 from the superior vestibular nerve otolith (SO), and 83 from the inferior nerve otolith (IO). Sound sensitivity of each afferent was quantified by computing the cumulative probability of evoking a spike (CPE). We found that clicks activated irregular afferents (normalized coefficient of variation of interspike intervals >0.2) from both the otoliths (81%) and the canals (43%). The order of end organ sound sensitivity was SO = IO > AC > HC > PC. Since the sternocleidomastoid motoneurons receive inputs from both the otoliths and the canals, these results provide evidence of a possible contribution from both of them to the click-evoked cVEMP.

Upregulation of fatty acid synthase (FASN), a key enzyme of de novo lipogenesis, is associated with metastasis in colorectal cancer (CRC). However, the mechanisms of regulation are unknown. Since angiogenesis is crucial for metastasis, we investigated the role of FASN in the neovascularization of CRC. The effect of FASN on tumor vasculature was studied in orthotopic CRCs, the chick embryo chorioallantoic membrane (CAM) and Matrigel plug models using immunohistochemistry, immunofluorescent staining and confocal microscopy. Cell secretion was evaluated by ELISA and antibody arrays. Proliferation, migration and tubulogenesis of endothelial cells (ECs) were assessed in CRC-EC coculture models. In this study, we found that stable knockdown of FASN decreased microvessel density in HT29 and HCT116 orthotopic CRCs and resulted in 'normalization' of tumor vasculature in both orthotopic and CAM models. Furthermore, FASN regulated secretion of pro- and antiangiogenic factors, including vascular endothelial growth factor-A (VEGF-A). Mechanisms associated with the antiangiogenic activity noted with knockdown of FASN included: downregulation of VEGF(189), upregulation of antiangiogenic isoform VEGF(165b) and a decrease in expression and activity of matrix metalloproteinase-9. Furthermore, conditioned medium from FASN knockdown CRC cells inhibited activation of vascular endothelial growth factor receptor-2 and its downstream signaling and decreased proliferation, migration and tubulogenesis of ECs as compared with control medium. Together, these results suggest that cancer cell-associated FASN regulates tumor vasculature through alteration of the profile of secreted angiogenic factors and regulation of their bioavailability. Inhibition of FASN upstream of VEGF-A and other angiogenic pathways can be a novel therapeutic strategy to prevent or inhibit metastasis in CRC.

Background The precise involvement of the PI3K/mTOR and RAS/MEK pathways in carcinoid tumors is not well defined. Therefore, the purpose of our study was to evaluate the role these pathways play in carcinoid cell proliferation, apoptosis, and secretion and to determine the effects of combined treatment on carcinoid tumor inhibition. Methods The human neuroendocrine cell lines BON (pancreatic carcinoid), NCI-H727 (lung carcinoid), and QGP-1 (somatostatinoma) were treated with either the pan-PI3K inhibitor, BKM120, or the dual PI3K-mTOR inhibitor, BEZ235, alone or in combination with the MEK inhibitor, PD0325901; proliferation, apoptosis, and protein expression were assessed. Peptide secretion was evaluated in BON and QGP-1 cells. The anti-proliferative effect of BEZ235, alone or combined with PD0325901, was then tested in vivo. Results Both BKM120 and BEZ235 decreased proliferation and increased apoptosis; combination with PD0325901 significantly enhanced the antineoplastic effects of either treatment alone. In contrast, neurotensin (NT) peptide secretion was markedly stimulated with BKM120 treatment, but not BEZ235. The combination of BEZ235 + PD0325901 significantly inhibited the growth of BON xenografts without systemic toxicity. Conclusions Both BKM120 and BEZ235 effectively inhibited NET cell proliferation and stimulated apoptosis. However, inhibition of the PI3K pathway alone with BKM120 significantly stimulated NT peptide secretion; this did not occur with the dual inhibition of both PI3K and mTOR using BEZ235 suggesting that this would be a more effective treatment regimen for NETs. Moreover, the combination of BEZ235 and the MEK inhibitor PD0325901 was a safe and more effective therapy in vivo compared with single agents alone.

In the rat TRAM model, surgical delay resulted in increased VEGF expression and increased skin paddle survival. These results correlate with previous studies showing the preoperative injection of VEGF increases skin paddle survival. VEGF may be an important element in the delay phenomenon and may be an agent for pharmacological delay.

Some individuals with noise-induced hearing loss (NIHL) also report balance problems. These accompanying vestibular complaints are not well understood. The present study used a rat model to examine the effects of noise exposure on the vestibular system. Rats were exposed to continuous broadband white noise (0–24kHz) at an intensity of 116dB sound pressure level (SPL) via insert ear phones in one ear for three hours under isoflurane anesthesia. Seven days after the exposure, a significant increase in ABR threshold (43.3±1.9dB) was observed in the noise-exposed ears, indicating hearing loss. Effects of noise exposure on vestibular function were assessed by three approaches. First, fluorescein-conjugated phalloidin staining was used to assess vestibular stereocilia following noise exposure. This analysis revealed substantial sensory stereocilia bundle loss in the saccular and utricular maculae as well as in the anterior and horizontal semicircular canal cristae, but not in the posterior semicircular canal cristae. Second, single unit recording of vestibular afferent activity was performed under pentobarbital anesthesia. A total of 548 afferents were recorded from 10 noise-treated rats and 12 control rats. Noise exposure produced a moderate reduction in baseline firing rates of regular otolith afferents and anterior semicircular canal afferents. Also a moderate change was noted in the gain and phase of the horizontal and anterior semicircular canal afferent’s response to sinusoidal head rotation (1 and 2Hz, 45 degrees/s peak velocity). Third, noise exposure did not result in significant changes in gain or phase of the horizontal rotational and translational vestibular-ocular reflex (VOR). These results suggest that noise exposure not only causes hearing loss, but also causes substantial damage in the peripheral vestibular system in the absence of immediate clinically measurable vestibular signs. These peripheral deficits, however, may lead to vestibular disorders over time.