Contribution of galectin-1, a glycan-binding protein, to gastrointestinal tumor progression

Gastrointestinal cancer is a group of tumors that affect multiple sites of the digestive system, including the stomach, liver, colon and pancreas. These cancers are very aggressive and rapidly metastasize, thus identifying effective targets is crucial for treatment. Galectin-1 (Gal-1) belongs to a family of glycan-binding proteins, or lectins, with the ability to cross-link specific glycoconjugates. A variety of biological activities have been attributed to Gal-1 at different steps of tumor progression. Herein, we summarize the current literature regarding the roles of Gal-1 in gastrointestinal malignancies. Accumulating evidence shows that Gal-1 is drastically up-regulated in human gastric cancer, hepatocellular carcinoma, colorectal cancer and pancreatic ductal adenocarcinoma tissues, both in tumor epithelial and tumor-associated stromal cells. Moreover, Gal-1 makes a crucial contribution to the pathogenesis of gastrointestinal malignancies, favoring tumor development, aggressiveness, metastasis, immunosuppression and angiogenesis. We also highlight that alterations in Gal-1-specific glycoepitopes may be relevant for gastrointestinal cancer progression. Despite the findings obtained so far, further functional studies are still required. Elucidating the precise molecular mechanisms modulated by Gal-1 underlying gastrointestinal tumor progression, might lead to the development of novel Gal-1-based diagnostic methods and/or therapies.Fil: Bacigalupo, Maria Lorena. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas ; ArgentinaFil: Carabias, Pablo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas ; ArgentinaFil: Troncoso, María Fernanda. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Química y Físico-Química Biológicas ; Argentin

Heparan sulfate proteoglycans undergo differential expression alterations in left sided colorectal cancer, depending on their metastatic character

Abstract Background Heparan sulfate proteoglycans (HSPGs) are complex molecules which play a role in the invasion and growth and metastatic properties of cancerous cells. In this work we analyze changes in the patterns of expression of HSPGs in left sided colorectal cancer (LSCRC), both metastatic and non-metastatic, and the results are also compared with those previously obtained for right sided tumors (RSCRCs). Methods Eighteen LSCRCs were studied using qPCR to analyze the expression of both the proteoglycan core proteins and the enzymes involved in heparan sulfate chain biosynthesis. Certain HSPGs also carry chondroitin sulfate chains and so we also studied the genes involved in its biosynthesis. The expression of certain genes that showed significant expression differences were also analysed using immunohistochemical techniques. Results Changes in proteoglycan core proteins were dependent on their location, and the main differences between metastatic and non-metastatic tumors affected cell-surface glypicans, while other molecules were quite similar. Glypicans were also responsible for the main differences between RS- and LS- malignances. Regarding the biosynthesis of heparan sulfate chains, differential alterations in transcription depending on the presence or not of metastasis affected genes involved in the modification of uronic acid (epimerization and 2-O sulfation), and some isoforms responsible for sulfation of glucosamine (NDST1, HS6ST1). Moreover, in RSCRCs differences were preferentially found in the expression of genes involved in C6 and C3 sulfation of glucosamine, but not in NDSTs or SULFs. Finally, synthesis of chondroitin sulfate showed some alterations, which affected various steps, including polimerization and the modification of chains, but the main variations dependent on the presence of metastases were epimerization and 6C sulfation; however, when compared with RSCRCs, the essential divergences affected polymerization of the chains and the 6C sulfation of the galactosamine residue. Conclusions We evidenced alterations in the expression of HSPGs, including the expression of cell surface core proteins, many glycosiltransferases and some enzymes that modify the GAG chains in LSCRCs, but this was dependent on the metastatic nature of the tumor. Some of these alterations are shared with RSCRCs, while others, focused on specific gene groups, are dependent on tumor localization

Long non-coding RNAs in cutaneous melanoma : clinical perspectives

Metastatic melanoma of the skin has a high mortality despite the recent introduction of targeted therapy and immunotherapy. Long non-coding RNAs (lncRNAs) are defined as transcripts of more than 200 nucleotides in length that lack protein-coding potential. There is growing evidence that lncRNAs play an important role in gene regulation, including oncogenesis. We present 13 lncRNA genes involved in the pathogenesis of cutaneous melanoma through a variety of pathways and molecular interactions. Some of these lncRNAs are possible biomarkers or therapeutic targets for malignant melanoma

Functional Effects of let-7g Expression in Colon Cancer Metastasis.

MicroRNA regulation is crucial for gene expression and cell functions. It has been linked to tumorigenesis, development and metastasis in colorectal cancer (CRC). Recently, the let-7 family has been identified as a tumor suppressor in different types of cancers. However, the function of the let-7 family in CRC metastasis has not been fully investigated. Here, we focused on analyzing the role of let-7g in CRC. The Cancer Genome Atlas (TCGA) genomic datasets of CRC and detailed data from a Taiwanese CRC cohort were applied to study the expression pattern of let-7g. In addition, in vitro as well as in vivo studies have been performed to uncover the effects of let-7g on CRC. We found that the expression of let-7g was significantly lower in CRC specimens. Our results further supported the inhibitory effects of let-7g on CRC cell migration, invasion and extracellular calcium influx through store-operated calcium channels. We report a critical role for let-7g in the pathogenesis of CRC and suggest let-7g as a potential therapeutic target for CRC treatment

Gelsolin induces colorectal tumor cell invasion via modulation of the urokinase-type plasminogen activator cascade

Gelsolin is a cytoskeletal protein which participates in actin filament dynamics and promotes cell motility and plasticity. Although initially regarded as a tumor suppressor, gelsolin expression in certain tumors correlates with poor prognosis and therapy-resistance. In vitro, gelsolin has anti-apoptotic and pro-migratory functions and is critical for invasion of some types of tumor cells. We found that gelsolin was highly expressed at tumor borders infiltrating into adjacent liver tissues, as examined by immunohistochemistry. Although gelsolin contributes to lamellipodia formation in migrating cells, the mechanisms by which it induces tumor invasion are unclear. Gelsolin’s influence on the invasive activity of colorectal cancer cells was investigated using overexpression and small interfering RNA knockdown. We show that gelsolin is required for invasion of colorectal cancer cells through matrigel. Microarray analysis and quantitative PCR indicate that gelsolin overexpression induces the upregulation of invasion-promoting genes in colorectal cancer cells, including the matrix-degrading urokinase-type plasminogen activator (uPA). Conversely, gelsolin knockdown reduces uPA levels, as well as uPA secretion. The enhanced invasiveness of gelsolin-overexpressing cells was attenuated by treatment with function-blocking antibodies to either uPA or its receptor uPAR, indicating that uPA/uPAR activity is crucial for gelsolin-dependent invasion. In summary, our data reveals novel functions of gelsolin in colorectal tumor cell invasion through its modulation of the uPA/uPAR cascade, with potentially important roles in colorectal tumor dissemination to metastatic sites

The expression of matrix metalloproteinase 9 and cathepsin B in gastric carcinoma is associated with lymph node metastasis, but not with postoperative survival.

Degradation components of basement membrane could be crucial for tumor invasion. A key role in this process has been assigned to cysteine proteases, i.e. cathepsins and matrix metalloproteinases. The purpose of this study was to investigate the relationship of the expression of MMP-9 and cathepsin B with tumor aggressiveness expressed by lymph node metastases and survival rates in gastric carcinoma patients. Slides of 5 mum-thick serial sections from 91 patients with primary gastric carcinoma were prepared and analyzed for MMP-9 and cathepsin B expression using anti-human monoclonal antibody (NCL-MMP-9 clone; dilution 1:40 and NCL-CATH-B clone; dilution 1:40). The patients were clinically monitored for 84 months. We found no association between the expression of MMP-9 and cathepsin B in main mass of tumor and patients' gender, tumor location, Lauren's classification or histological differentiation. Also no correlation was observed between the expression of MMP-9 in main mass of tumor and depth of invasion. A strong statistically significant association was found between the expression of MMP-9 and cathepsin B in main mass of tumor and lymph node involvement (

Correlation of Neuroendocrine Differentiation with Neuroendocrine Cell Hyperplasia and Vascular Endothelial Growth Factor in Colorectal Adenocarcinoma

تم ذكر تمايز الغدد الصم العصبية في العديد من سرطانات الأعضاء غير الغدد الصماء العصبية ، والتي تشمل الجهاز الهضمي. في المقابل ، لم يتم التطرق عن وجود علاقة بين تمايز الغدد الصم العصبية المنتشر بؤريا في سرطان القولون والمستقيم مع تضخم خلايا الغدد الصم العصبية. تهدف هذه الدراسة إلى إيجاد العلاقة بين تمايز الغدد الصم العصبية وتضخم خلايا الغدد الصم العصبية ، ولایجاد علاقة تمايز الغدد الصم العصبية والتعبير عن عامل نمو بطانة الأوعية الدموية مع العوامل الإكلينيكية والنسيجية في سرطان القولون والمستقيم. كانت الطرق المستخدمة في الدراسة الحالية تضمنت واحدة وثمانون مریضا بسرطان القولون والمستقيم. تم تقطیع الكتل النسیجیة المضمنة من البارافين والمثبتة بالفورمالين وتم تصبیغها بكل من العلامات المناعية الكيميائية ؛ Chromogranin A و VEGF. وتمت معالجتها تلقائيًا وفقًا للبروتوكولات التي وفرتها الشركة المصنعة للجسم المضاد. أظهرت النتائج أن تضخم خلايا الغدد الصم العصبية في الغشاء المخاطي القريب من الورم يتألف من 42 ٪ وكانت لها علاقة مع تمايز الغدد الصم العصبية. كانت تمايز الغدد الصم العصبية وعامل نمو بطانة الأوعية الدموية إيجابية في 48.1 ٪ و 63 ٪ على التوالي. لم تظهر تمايز الغدد الصم العصبية علاقة مع المعلمات الإكلينيكية باستثناء مرحلة الورم التي تغزو إلى الأنسجة والأعضاء الأخرى. وكانت علاقة ارتباط عامل نمو بطانة الأوعية الدموية مع نفس العوامل ذو تأثير كبير مع مرحلة الورم ، درجة انتشار الورم فی الأنسجة القریبە وانتشاره فی العقد الليمفاوية. التغيرات النسيجية الأخرى اظهرت ان رد فعل دسموبلاستيك فقط كان له فرق معنوي كبير في العلاقة مع التمايز العصبي. توصلت هذه الدراسة إلى استنتاج مفاده أن تضخم خلايا الغدد الصم العصبية کان مرتبطا بتمايز الغدد الصم العصبية وله علاقة قوية مع امراضیة سرطان القولون والمستقيم. ترتبط تمايز الغدد الصم العصبية ، والتعبيرعن عامل نمو البطانة الوعائي إلى حد كبير مع تطور وانتشار الورم فی انسجة واعضاء اخرى ، وهذا یمکن ان یمثل عامل غیر جید للتنبۆ بتطور المرض في سرطان القولون والمستقيم.  Neuroendocrine differentiation has been mentioned in many cancers of non-neuroendocrinal organs, involving the gastrointestinal tract. In contrast, the correlation of focally diffused neuroendocrine differentiation in colorectal adenocarcinoma with neuroendocrine cell hyperplasia has not been somewhat reported. The objective of this research is to study the relationship between neuroendocrine cell hyperplasia and neuroendocrine differentiation in colorectal adenocarcinoma and to find the correlation of neuroendocrine differentiation and VEGF expression with clinicopathological parameters of colorectal adenocarcinoma. Methods employed in the current study were including eighty-one patients with colorectal cancer. Formalin fixed paraffin embedded blocks were sectioned and stained with immunohistochemical markers; Chromogranin A and VEGF; and processed automatically according to protocols supplied by the antibody manufacturer. Results show that neuroendocrine cell hyperplasia in the mucosa nearby tumor comprised (42%) and it was associated with neuroendocrine differentiation. Neuroendocrine differentiation and vascular endothelial growth factor were positive in 48.1% and 63% respectively. Neuroendocrine differentiation did not show a relation with clinicopathological parameters with the exception of tumor that metastasizes to other tissues and organs. The association of VEGF with the same factors had significant impact with tumor stage, degree of local invasion and lymph node metastasis. Other histological changes revealed that only desmoplastic reaction had significant difference in relation to neuroendocrine differentiation. This study reached the conclusion that neuroendocrine cell hyperplasia is positively correlated with neuroendocrine differentiation and it has strong linkage in pathogenesis of colorectal adenocarcinoma. Neuroendocrine differentiation and VEGF expression are greatly correlated with progression and invasion of tumor to other tissues and organs, and this can be represented as an important parameter for poor prognosis of colorectal adenocarcinoma

Role of Cancer Microenvironment in Metastasis: Focus on Colon Cancer

One person on three will receive a diagnostic of cancer during his life. About one third of them will die of the disease. In most cases, death will result from the formation of distal secondary sites called metastases. Several events that lead to cancer are under genetic control. In particular, cancer initiation is tightly associated with specific mutations that affect proto-oncogenes and tumour suppressor genes. These mutations lead to unrestrained growth of the primary neoplasm and a propensity to detach and to progress through the subsequent steps of metastatic dissemination. This process depends tightly on the surrounding microenvironment. In fact, several studies support the point that tumour development relies on a continuous cross-talk between cancer cells and their cellular and extracellular microenvironments. This signaling cross-talk is mediated by transmembrane receptors expressed on cancer cells and stromal cells. The aim of this manuscript is to review how the cancer microenvironment influences the journey of a metastatic cell taking liver invasion by colorectal cancer cells as a model

Seprase: An overview of an important matrix serine protease

Seprase or Fibroblast Activation Protein (FAP) is an integral membrane serine peptidase, which has been shown to have gelatinase activity. Seprase has a dual function in tumour progression. The proteolytic activity of Seprase has been shown to promote cell invasiveness towards the ECM and also to support tumour growth and proliferation. Seprase appears to act as a proteolytically active 170-kDa dimer, consisting of two 97- kDa subunits. It is a member of the group type II integral serine proteases, which includes dipeptidyl peptidase IV (DPPIV/CD26) and related type II transmembrane prolyl serine peptidases, which exert their mechanisms of action on the cell surface. DPPIV and Seprase exhibit multiple functions due to their abilities to form complexes with each other and to interact with other membrane-associated molecules. Localisation of these protease complexes at cell surface protrusions, called invadopodia, may have a prominent role in processing soluble factors and in the degradation of extracellular matrix components that are essential to the cellular migration and matrix invasion that occur during tumour invasion, metastasis and angiogenesis