Low Metastatic Potential Research Articles

Toll-like receptor 4 prompts human breast cancer cells invasiveness via lipopolysaccharide stimulation and is overexpressed in patients with lymph node metastasis.

Toll-like receptor (TLR)4-mediated signaling has been implicated in tumor cell invasion, survival, and metastasis in a variety of cancers. This study investigated the expression and biological role of TLR4 in human breast cancer metastasis. MCF-7 and MDA-MB-231 are human breast cancer cell lines with low and high metastatic potential, respectively. Using lipopolysaccharide (LPS) to stimulate MCF-7 and MDA-MB-231 cells, expression of TLR4 mRNA and protein increased compared with that in control cells. TLR4 activation notably up-regulated expression of matrix metalloproteinase (MMP)-2, MMP-9 and vascular endothelial growth factor(VEGF) mRNA and their secretion in the supernatants of both cell lines. LPS enhanced invasion of MDA-MB-231 cells by transwell assay and MCF-7 cells by wound healing assay. LPS triggered increased expression of TLR4 downstream signaling pathway protein myeloid differentiation factor 88(MyD88) and resulted in interleukin (IL)-6 and IL-10 higher production by human breast cancer cells. Stimulation of TLR4 with LPS promoted tumorigenesis and formed metastatic lesions in liver of nude mice. Moreover, expression of TLR4 and MyD88 as well as invasiveness and migration of the cells could be blocked by TLR4 antagonist. Combined with clinicopathological parameters, TLR4 was overexpressed in human breast cancer tissue and correlated with lymph node metastasis. These findings indicated that TLR4 may participate in the progression and metastasis of human breast cancer and provide a new therapeutic target.

Abstract LB-102: A tumor-specific tissue penetrating peptide inhibits metastasis

Abstract Neuropilin-binding tumor-penetrating peptides increase vascular and tissue permeability in tumors, allowing drugs conjugated to the peptide and even free drugs co-injected with the peptide to widely distribute within the tumor tissue (Sugahara KN et al, Cancer Cell 16:510, 2009; Science 328:1031, 2010). Thus, the peptides provide an elegant way to enhance therapeutic index of anti-cancer drugs. However, the ability of the peptides to increase vascular permeability has raised concerns that the peptides might enhance metastasis by promoting cell seeding from the primary tumor. Here, we show a recent unexpected finding that a prototypic tumor-penetrating peptide, iRGD (amino acid sequence: CRGDK/RGPD/EC), is a potent metastasis inhibitor. iRGD did not cause systemic tumor cell dissemination or metastasis in mice bearing breast tumors with low metastatic potential. iRGD treatment of mice bearing aggressive orthotopic pancreatic tumors resulted in significant decrease in spontaneous metastasis formation. Primary tumor growth was not affected by the treatment. Another tumor-penetrating peptide, iNGR, also inhibited metastasis, while conventional RGD peptides or a scrambled iRGD peptide that lack neuropilin affinity failed to do. These results indicate that the anti-metastatic effect of iRGD was dependent on its neuropilin-binding peptide motif. In vitro migration assays demonstrated that iRGD potently inhibits tumor cell migration and serves as a chemorepellent of tumor cells in a neuropilin-dependent manner. Chemorepulsion assays based on live cell imaging confirmed the findings, and further demonstrated that iRGD dramatically collapses tumor cell protrusions leading to an instantaneous retraction of tumor cells from iRGD-bound surfaces. Our finding refutes the hypothesis that iRGD may cause enhanced metastasis. The mechanism of the anti-metastatic effect may involve neuropilin-mediated chemorepulsion of tumor cells. Collectively, iRGD may simultaneously achieve tumor-specific drug delivery and metastasis inhibition when utilized for cancer treatment. Citation Format: Kazuki N. Sugahara, Gary B. Braun, Tatiana H. de Mendoza, Venkata R. Kotamraju, Tambet Teesalu, Erkki Ruoslahti, Randall P. French, Andrew M. Lowy. A tumor-specific tissue penetrating peptide inhibits metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr LB-102. doi:10.1158/1538-7445.AM2014-LB-102

Abstract 42: TRPM7 expression predicts poor prognosis in patients with nasopharyngeal carcinoma and correlates with tumor metastasis

Abstract The aim of this study was to investigate prognostic significance of TRPM7 expression in nasopharyngeal carcinoma (NPC) and evaluate the association of TRPM7 with tumor invasion and metastasis. Immunohistochemical staining for TRPM7 was carried out on paraffin-embedded tissue sections from 206 NPC patients. The data was subjected to statistical analysis with respect to clinicopathological variables and survival. Real-time PCR and Western blot were used to assess the expression of TRPM7 in NPC cells. Small interfering RNA and construct transfection were used to knockdown and improve TRPM7 expression in NPC cells. TRPM7 was highly expressed in 102 out of 206 (49.5%) NPC cases. TRPM7 expression was significantly correlated with clinical stage, lymphatic and distant metastasis. The patients who had high TRPM7 expression showed a significantly lower 5 year survival rate than the patients who had low TRPM7 expression. TRPM7 might be an independent prognostic indicator for patient's survival. The cell lines with high metastatic potential expressed more TRPM7 than the cell lines with low metastatic potential. Moreover, the migratory and invasive potential of NPC cells was significantly decreased and increased by TRPM7 knockdown and overexpression. The study indicates that TRPM7 expression is inversely correlated with NPC patient survival and correlated with NPC invasion and metastasis. Note: This abstract was not presented at the meeting. Citation Format: Jian-Peng Chen, Guiqin Sun, Wei-Bo Wang, Cai-Xia Wang. TRPM7 expression predicts poor prognosis in patients with nasopharyngeal carcinoma and correlates with tumor metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 42. doi:10.1158/1538-7445.AM2014-42

Abstract 4882: Expression profiles of proinflammatory chemokines in prostate cancer cell supernatants

Abstract Background: Prostate cancer progression is a complex process in which chemokines and their receptors play an important role related to tumor survival, growth, and metastasis. Objectives: 1) To determine the expression profiles of proinflammatory chemokines in prostate cancer cell line supernatants and their association with the metastatic phenotype, and 2) To determine whether these chemokines are present in the exosomes released from prostate cancer cell lines examined. Methods: Prostate cancer lines investigated included PWR-1E (non-tumorigenic), LNCaP (low metastatic potential) and PC-3 (high metastatic potential). The Human Common Chemokines Multi-Analyte ELISArray Kit (Qiagen) was used to evaluate the expression profiles of several proinflammatory chemokines in the supernatant and in the exosomal fraction of prostate cancer cells in culture. Chemokine profiles were correlated with the metastatic abilities of the cell lines analyzed. Chemokines evaluated were CCL2, CCL3, CCL4, CCL5, CCL11, CCL17, CCL22, CXCL1, CXCL8, CXCL9, CXCL10 and CXCL11. Results: Differential chemokine profiles in the cell lines were observed in the supernatant and in the exosomal fractions. Conclusions: Prostate cancer cell lines with different phenotypes have different chemokine profiles, both in supernatant and in the exosomal fraction of these cells in culture. These results may be useful for the design of diagnostic, prognostic and/ or therapeutic strategies. Financial support: Universidad de Cartagena Project Code: Res 04670 - 2012 Citation Format: Niradiz Reyes, Oscar Correa, Alfonso Bettin, Raj K. Tiwari, Jan Geliebter. Expression profiles of proinflammatory chemokines in prostate cancer cell supernatants. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4882. doi:10.1158/1538-7445.AM2014-4882

The impact of tumour size on the probability of synchronous metastasis and survival in renal cell carcinoma patients: a population-based study.

BackgroundThe observed low metastatic potential and favorable survival of small incidentally detected renal cell carcinomas (RCCs) have been a part of the rationale for recommending partial nephrectomy as a first treatment option and active surveillance in selected patients. We examined the relationship between tumor size and the odds of synchronous metastases (SMs) (primary outcome) and disease specific survival (secondary outcome) in a nationwide RCC registry.MethodsRetrospective study of the 794 RCC patients diagnosed in Iceland between 1971 and 2005. Histological material and TNM staging were reviewed centrally. The presence of SM and survival were recorded. Cubic spline analysis was used to assess relationship between tumor size and probability of SM. Univariate and multivariate statistics were used to estimate prognostic factors for SM and survival.ResultsThe probability of SM increased in a non-linear fashion with increasing tumor size (11, 25, 35, and 50%) for patients with tumors of ≤4, 4.1-7.0, 7.1-10.0, and >10 cm, respectively. On multivariate analysis, tumor size was an independent prognostic factor for disease-specific survival (HR = 1.05, 95% CI 1.02-1.09, p < 0.001), but not for SM.ConclusionTumor size affected the probability of disease-specific mortality but not SM, after correcting for TNM staging in multivariate analysis. This confirms the prognostic ability of the 2010 TNM staging system for renal cell cancer in the Icelandic population.

The iron chelator Dp44mT inhibits hepatocellular carcinoma metastasis via N-Myc downstream-regulated gene 2 (NDRG2)/gp130/STAT3 pathway.

Here we showed that hepatocellular carcinoma (HCC) cell lines with high metastatic potential had low levels of NDRG2. The iron chelator Dp44mT up-regulated NDRG2, suppressed epithelial-mesenchymal transition (EMT) and inhibited tumor metastasis in HCC having high metastatic potential. Also Dp44mT attenuated the TGF-β1-induced EMT in HCC having low metastatic potential. In agreement, silencing endogenous NDRG2 with shNDRG2 in HCC cells attenuated the effect of Dp44mT. We showed that the NDRG2/gp130/STAT3 pathway can mediate Dp44mT effects. In agreement, we found that a combination of NDRG2 expression and p-STAT3 levels is a strong predictor of prognosis in HCC patients. We suggest that up-regulation of NDRG2 by Dp44mT is a promising therapeutic approach in HCC.

Secretomes are a potential source of molecular targets for cancer therapies and indicate that APOE is a candidate biomarker for lung adenocarcinoma metastasis.

Identifying patients at high risk of metastasis is a major challenge in lung adenocarcinoma (ADC) therapy, therefore discovery of noninvasive biomarkers and therapeutic targets is urgent. We found significant differences between the secretomes of differentially expressed proteins in lung ADC cell lines, clinical tissue samples and serum plasma samples with high and low metastatic potential. In particular, Apolipoprotein E (APOE) levels were three-times greater in cells with lymph node metastases (LNM) than those without. Our study indicates that APOE is a potential indicator of metastatic lung ADC and that secretomes may offer a valuable resource for biomarkers of lung ADC with LNM.

Diagnosis and Treatment of Neuroendocrine Lung Tumors

Pulmonary neuroendocrine tumors (PNT) encompass a broad spectrum of tumors including typical carcinoid (TC) and atypical (AC) tumors, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Although no variety can be considered benign, AC and TC have a much lower metastatic potential, are usually diagnosed in early stages, and most are candidates for surgical treatment. Several chemotherapy (CT) regimens are available in the case of recurrence or in advanced stages, although scientific evidence is insufficient. LCNEC, which is currently classified alongside large-cell carcinomas, have molecular features, biological behavior and CT sensitivity profile closely resembling SCLC. Pathological diagnosis is often difficult, despite the availability of immunohistochemical techniques, and surgical specimens may be necessary. The diagnostic tests used are similar to those used in other lung tumors, with some differences in the optimal tracer in positron emission tomography. The new TNM classification is useful for staging these tumors. Carcinoid syndrome, very rare in PNT, may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs. Overall, with the exception of SCLC, new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage.

Inhibition of annexin A7 gene and protein induces the apotosis and decreases the invasion, migration of the hepatocarcinoma cell line

Our previous studies have shown that annexin A7 (ANXA7) gives different expressions in the mouse hepatocarcinoma cell lines with low or high lymphatic metastatic potential in both gene and protein levels. In this study, whether by using RNA interference (RNAi) technique downregulating ANXA7 in the gene level or by using antibody against ANXA7 in the protein level, the depressed expression of ANXA7 could induce apotosis and decrease the invasion, migration capacities of the Hca-P cell, a hepatocarcinoma cell line with low lymphatic metastatic potential in vitro. The results indicate that ANXA7 is an important factor in tumors with the lymphatic metastasis.

ORAL VERRUCOUS CARCINOMA: A REPORT OF THREE CASES

Ackerman’s tumor is a low grade variant of oral Verrucous carcinoma (VC) or squamous cell carcinoma (OSCC). Although it occurs in other anatomic sites, most intraoral cases involve buccal mucosa, alveolar mucosa and gingiva. The typical features of VC that differ from the usual oral epidermoid carcinoma is it generally slow growing, chiefly exophytic and superficially invasive at until late in the course of the disease and have low metastatic potential. This paper presents three variable cases of oral VC along with their clinical and histo-pathological features.

Modulation of activity of known cytotoxic ruthenium(III) compound (KP418) with hampered transmembrane transport in electrochemotherapy in vitro and in vivo.

To increase electrochemotherapy (ECT) applicability, the effectiveness of new drugs is being tested in combination with electroporation. Among them two ruthenium(III) compounds, (imH)[trans-RuCl4(im)(DMSO-S)] (NAMI-A) and Na[trans-RuCl4(ind)2] (KP1339), proved to possess increased antitumor effectiveness when combined with electroporation. The objective of our experimental work was to determine influence of electroporation on the cytotoxic and antitumor effect of a ruthenium(III) compound with hampered transmembrane transport, (imH)[trans-RuCl4(im)2] (KP418) in vitro and in vivo and to determine changes in metastatic potential of cells after ECT with KP418 in vitro. In addition, platinum compound cisplatin (CDDP) and ruthenium(III) compound NAMI-A were included in the experiments as reference compounds. Our results show that electroporation leads to increased cellular accumulation and cytotoxicity of KP418 in murine melanoma cell lines with low and high metastatic potential, B16-F1 and B16-F10, but not in murine fibrosarcoma cell line SA-1 in vitro which is probably due to variable effectiveness of ECT in different cell lines and tumors. Electroporation does not potentiate the cytotoxicity of KP418 as prominently as the cytotoxicity of CDDP. We also showed that the metastatic potential of cells which survived ECT with KP418 or NAMI-A does not change in vitro: resistance to detachment, invasiveness, and re-adhesion of cells after ECT is not affected. Experiments in murine tumor models B16-F1 and SA-1 showed that ECT with KP418 does not have any antitumor effect while ECT with CDDP induces significant dose-dependent tumor growth delay in the two tumor models used in vivo.

Fusion of HepG2 cells with mesenchymal stem cells increases cancer‑associated and malignant properties: an in vivo metastasis model.

In the present study, we have tested the hypothesis that fusion between an altered cell and a mesenchymal stem cell produces a hybrid cell with enhanced characteristics associated with metastatic cancer cells, and we have developed a flexible model for investigating the mechanisms of metastasis. Human HepG2 cells with low metastatic potential were induced to fuse with rat bone marrow mesenchymal stem cells, and the progeny were compared with the parental cells for possession of enhanced in vitro and in vivo characteristics of malignant cells. Compared to the parental cells, the fused cells exhibited enhanced expression of E-cadherin, vimentin, Twist, Snail, matrix metalloproteinase 2 and 9 activities, aneuploidy and enhanced in vitro invasion and migration. In an in vivo xenograft assay, the fused cells generated increased numbers of metastatic liver and lung lesions. This model system is a flexible tool for investigation of the mechanisms of stem cell fusion in carcinogenesis and metastasis and for the discovery of new therapeutic targets to inhibit metastasis.

Nucleolin identified by comparative mass‑spectra analysis is a potential marker for invasive progression of hepatocellular carcinoma.

At present, the diagnosis and prognosis of hepatocellular carcinoma (HCC) metastasis remains poor. Recently, a number of proteins associated with the metastasis and invasion of HCC were identified; however, the effective markers require further elucidation. In the current study, a nucleolin expression was observed in MHCC97L and HCCLM9 HCC cell lines, with low and high metastatic potentials respectively, using comparative proteomics. The data indicated that nucleolin expression in the nucleus was significantly higher in HCCLM9 cells, and it primarily influenced the migration of HCC cells in vitro. Thus, to the best of our knowledge this is the first study to hypothesize that nucleolin may be a novel marker for HCC invasive progression.

Identifying metabolomic features that predict metastasis of melanoma from a primary site

Background About 90% of mortality associated with cancer is attributable to metastatic disease. Thus, our ability to treat cancer is largely dependent on the capacity to prevent metastasis. Metabolic reprogramming is recognized to support cellular transformation and tumor initiation; however, whether or how metabolism supports metastasis remains an open question. This study seeks to identify metabolic predictors of metastasis, with the rationale that understanding metabolic changes will lead to novel insights into metastasis and perhaps new therapies to treat metastatic disease. Materials and methods A patient-derived xenograft model was used in which metastasis in mice strongly correlates with metastatic history of patient donors. Tumor cells were originally obtained from melanoma patients and passaged exclusively in highly immunocompromised mice [1]. In this study, 17 of such tumor lines were investigated including 6 lines with low metastatic potential, 9 high metastatic potential and 2 intermediate metastatic potential. Tumor cells were implanted subcutaneously into mice, yielding 62 tumors. 3-4 biopsies from each primary tumor were harvested, for a total of 185 samples. A mass spectrometry (MS)-based analytical platform was used to characterize >150 metabolites in each specimen. The relative abundance of metabolites that contribute most to the distinction of highly metastatic from inefficiently metastatic melanomas was examined using statistical tools. Results Unsupervised hierarchical clustering revealed that in every case, a given tumor biopsy was most closely related to all other biopsies descended from the same parental tumor. In addition, as a frequent mutation in melanoma, BRAFmutant tumors were easily distinguished from BRAF-wild type tumors by their metabolomic signatures. More importantly, several metabolic pathways were found altered significantly when metabolomics profiles between melanoma lines with high or low metastatic potentials were compared. Conclusions The MS-based metabolomic analysis of patient-derived melanoma xenografts demonstrates that tumors contain individual metabolomic identities that can be tracked. It may be possible to identify metabolomic features from primary tumors that predict various aspects of tumor biology, including the propensity to metastasize. The altered metabolic pathways in highly metastatic melanomas are potential therapeutic targets.

The contemporary role of ablative treatment approaches in the management of renal cell carcinoma (RCC): focus on radiofrequency ablation (RFA), high-intensity focused ultrasound (HIFU), and cryoablation

Currently, most of renal tumors are small, low grade, with a slow growth rate, a low metastatic potential, and with up to 30 % of these tumors being benign on the final pathology. Moreover, they are often diagnosed in elderly patients with preexisting medical comorbidities in whom the underlying medical conditions may pose a greater risk of death than the small renal mass. Concerns regarding overdiagnosis and overtreatment of patients with indolent small renal tumors have led to an increasing interest in minimally invasive, ablative as an alternative to extirpative interventions for selected patients. To provide an overview about the state of the art in radiofrequency ablation (RFA), high-intensity focused ultrasound, and cryoablation in the clinical management of renal cell carcinoma. A PubMed wide the literature search of was conducted. International consensus panels recommend ablative techniques in patients who are unfit for surgery, who are not considered candidates for or elect against elective surveillance, and who have small renal masses. The most often used techniques are cryoablation and RFA. These ablative techniques offer potentially curative outcomes while conferring several advantages over extirpative surgery, including improved patient procedural tolerance, faster recovery, preservation of renal function, and reduction in the risk of intraoperative and postsurgical complications. While it is likely that outcomes associated with ablative modalities will improve with further advances in technology, their application will expand to more elective indications as longer-term efficacy data become available. Ablative techniques pose a valid treatment option in selected patients.

Verrucous carcinoma of the foot, not your typical plantar wart: A case study

Statement of purposeVerrucous carcinoma of the foot is often misdiagnosed initially as plantar warts. Delayed diagnostic treatments with the use of optimal biopsy techniques may result in significant hindrances for patient care and may often result in detrimental outcomes to the patient. With the use of various epidermal biopsy methods, early diagnostic treatment can be implemented to a slow-growing lesion unresponsive to topical agents preventing unfavorable pedal amputations. DesignA case study of verrucous carcinoma of the foot with surgical resection was conducted along with a literature review. BackgroundVerrucous carcinoma (VC) of the foot is known to be a rare, locally invasive, well-differentiated low-grade squamous cell carcinoma that may evolve from the human papilloma virus. This localized tumor of the foot often has low metastatic potential, however can be quite invasive. It is therefore pertinent to obtain adequate radiological studies when planning for surgical resection of this tumor. When localized to the foot, it often involves deep structures such as tendons, muscle & bone. Complete wide local excision of the tumor is essential to avoid recurrence. We present a case of verrucous carcinoma of the foot in a 46-year-old African American male with a past medical history of Human immunodeficiency virus (HIV) and Human papilloma virus (HPV). The patient refused a Transmetatarsal amputation. The loss of the third digit was a result of tissue loss following resection and an attempt to relocate a severely laterally dislocated 3rd digit, not PVD.

Diagnóstico y tratamiento de los tumores pulmonares neuroendocrinos

Pulmonary neuroendocrine tumors (PNT) encompass a broad spectrum of tumors including typical carcinoid (TC) and atypical (AC) tumors, large-cell neuroendocrine carcinoma (LCNEC) and small-cell lung cancer (SCLC). Although no variety can be considered benign, AC and TC have a much lower metastatic potential, are usually diagnosed in early stages, and most are candidates for surgical treatment. Several chemotherapy (CT) regimens are available in the case of recurrence or in advanced stages, although scientific evidence is insufficient. LCNEC, which is currently classified alongside large-cell carcinomas, have molecular features, biological behavior and CT sensitivity profile closely resembling SCLC. Pathological diagnosis is often difficult, despite the availability of immunohistochemical techniques, and surgical specimens may be necessary. The diagnostic tests used are similar to those used in other lung tumors, with some differences in the optimal tracer in positron emission tomography. The new TNM classification is useful for staging these tumors. Carcinoid syndrome, very rare in PNT, may cause symptoms that are difficult to control and requires special therapy with somatostatin analogs and other drugs. Overall, with the exception of SCLC, new trials are needed to provide a response to the many questions arising with regard to the best treatment in each lineage and each stage.

Nasopharyngeal Hyalinizing Clear Cell Carcinoma

Hyalinizing clear cell carcinoma (HCCC) is a rare low-grade malignant tumor affecting the minor salivary glands; nasopharyngeal involvement is uncommon. A 38-year-old male patient presented with a 3.2 × 4.5 × 4.4 cm expansile mass obliterating the lumen of the nasopharynx and extending into the left nasal cavity. Histopathologically, the tumor was characterized by clear round to polygonal epithelial cells arranged in anastomosing trabeculae and solid nests. The stroma consisted of fibromyxoid connective tissue with areas of intense hyalinization and desmoplasia. Immunohistochemically, strong and diffuse reactivity for AE1/AE3, CK5/6, and p63 was observed. EWSR1 gene rearrangement was confirmed by fluorescence in situ hybridization. The diagnosis of nasopharyngeal HCCC was rendered. Surgical excision was performed along with adjuvant radiotherapy and chemotherapy. HCCC generally demonstrates good prognosis with low metastatic potential. Identification of EWSR1 gene disruption is usefulin discerning HCCC from other neoplasms with overlapping microscopic features.

Esophageal Stenosis Caused by a Rare Entity

Question: A 45-year-old man presented in our surgical department with progressive dysphagia for solids and liquids and weight loss over the last 6 month, he had a long history of tobacco abuse (25 pack-years), but no history of trauma or alcohol use. Physical examination showed his cachexia, but was otherwise unremarkable without palpable lymphadenopathy. He had been treated with long-term bouginage over 4 years for a long segment esophageal stenosis starting 30 cm distal to the dental arch. Repeatedly performed biopsies over that time course had been nondiagnostic, with only chronic inflammation and hyperkeratosis. He presented in our institution owing to shorter bouginage intervals and weight loss. Upper endoscopy showed a thickened, white, contact-vulnerable, exophytic, and lumen-constricting polypoid mass in the esophagus over a distance of 15 cm (Figure A; star = esophageal lumen). Multiple deep biopsies were taken; they revealed keratosis and chronic inflammation but no evidence of malignancy. The subsequent computed tomography with contrast enhancement revealed a long-segment thickening of the thoracic esophagus (Figure B, arrows) without any lymphadenopathy or metastases. What is the most likely diagnosis? Look on page 871 for the answer and see the Gastroenterology web site (www.gastrojournal.org) for more information on submitting your favorite image to Clinical Challenges and Images in GI. The verrucous carcinoma (VC) of the esophagus is a rare, well-differentiated, squamous cell carcinoma with about 20 cases described worldwide. It is associated with long-term local inflammation; tobacco abuse1Alkan A. Bulut E. Gunhan O. et al.Oral verrucous carcinoma: a study of 12 cases.Eur J Dentistry. 2010; 4: 202-207Crossref PubMed Google Scholar and recent studies suggest a potential role for human papillomavirus in carcinogenesis.2Viera C.L. Lopes J.C. Velosa J. A case of esophageal squamous cell carcinoma with positive HPV 11.Gastroenterol Hepatol. 2013; 36: 311-315Crossref PubMed Scopus (12) Google Scholar Despite its high degree of differentiation and slow growth, the outcome of patients with VC is unsatisfactory owing to late diagnosis and perioperative complications.3Osborn N.K. Keate R.F. Trastek V.F. et al.Verrucous carcinoma of the esophagus: clinicopathophysiologic features of a rare entity.Dig Dis Sci. 2003; 48: 465-474Crossref PubMed Scopus (42) Google Scholar Local invasion and its spread within the submucosa and paraesophageal layer leave it invisible for superficial biopsies, which usually show nonspecific acanthosis and hyperkeratosis associated with acute or chronic inflammation. The tumor invades the surrounding tissue, grows locally destructive, and has a very low potential for metastasis. Typical endoscopic appearances—mostly the only “proof” for this malignancy—include wart-like polypous, exophytic, spiked, or cauliflower like masses.3Osborn N.K. Keate R.F. Trastek V.F. et al.Verrucous carcinoma of the esophagus: clinicopathophysiologic features of a rare entity.Dig Dis Sci. 2003; 48: 465-474Crossref PubMed Scopus (42) Google Scholar Surgery is adequate therapy for early stages that are locally resectable; patients with esophageal VC do not benefit from chemotherapy. Our patient underwent thoracoabdominal esophagectomy. Intraoperatively, we found a thin, dilated, proximal esophagus with a thick wall in the stenotic area and inflamed adhesion to the mediastinum. The macroscopic pathological specimen showed the strong hyperkeratotic, exophytic growth of the tumor (Figure C, arrows); final histology revealed the VC of the esophagus pT2, pN0, L0, V0, Pn0, R0, G1. The microscopic image displays the invasive component of the squamous cell carcinoma (Figure D, arrow). The patient was dismissed after an uneventful postoperative course on postoperative day 15. VC of the esophagus is not only a rare entity, its preoperative diagnosis also is extraordinary challenging and relies on clinical suspicion induced by typical endoscopic appearance. An esophageal resection should be performed in case of severe, progressive dysphagia in combination with typical endoscopic appearance even without histologic proof, because definitive diagnosis can mostly first be seen in the resected specimen.

Silencing of LASS2/TMSG1 enhances invasion and metastasis capacity of prostate cancer cell

Homo sapiens longevity assurance homolog 2 of yeast LAG1 (LASS2), also known as tumor metastasis suppressor gene 1 (TMSG1), was firstly cloned by our laboratory in 1999. However, its antitumor molecular mechanisms are still unclear. LASS2/TMSG-1 could directly interact with the C subunit of Vacuolar H(+) ATPase (V-ATPase), which suggested that LASS2/TMSG1 might inhibit the invasion and metastasis through regulating the function of V-ATPase. In this study, we explored the effect of small hairpin RNA (shRNA) targeting LASS2/TMSG1 on the invasion and metastasis of human prostate carcinoma cell line PC-3M-2B4 with low metastatic potential and its functional interaction with V-ATPase. Silencing of LASS2/TMSG1 gene in PC-3M-2B4 cells increased V-ATPase activity, extracellular hydrogen ion concentration and in turn the activation of secreted MMP-2 and MMP-9, which coincided with enhancing cell proliferation, cell survival, and cell invasion in vitro, as well as acceleration of prostate cancer (PCA) growth and lymph node metastases in vivo. Thus we concluded that silencing of LASS2/TMSG1 enhances invasion and metastasis of PCA cell through increase of V-ATPase activity. These results establish LASS2/TMSG1 as a promising therapeutic target for advanced PCA.