Colorectal Cancer Stem Cell Biomarkers: Biological Traits and Prognostic Insights.

Due to self-renewal, differentiation, and limitless proliferation properties, Cancer Stem Cells (CSCs) increase the probability of tumor development. These cells are identified by using CSC markers, which are highly expressed proteins on the cell surface of CSCs. Recently, the therapeutic application of CSCs as novel biomarkers improved both the prognosis and diagnosis outcome of colorectal Cancer. In the present review, we focused on a specific panel of colorectal CSC markers, including LGR5, ALDH, CD166, CD133, and CD44, which offers a targeted and comprehensive analysis of their functions. The selection criteria for these markers cancer were based on their established significance in Colorectal Cancer (CRC) pathogenesis and clinical outcomes, providing novel insights into the CSC biology of CRC. Through this approach, we aim to elevate understanding and stimulate further research for developing effective diagnostic and therapeutic strategies in CRC.

Therapeutic potency of A1 adenosine receptor antagonists in the treatment of cardiovascular diseases, current status and perspectives.

BACKGROUND: Cardiomyocytes form, transport, and metabolize the omnipresent metabolite adenosine. Depending upon the adenosine concentrations and the pharmacological properties of receptor subtypes, adenosine exerts (patho)physiological responses in the cardiovascular system. The objective of this review is to present different protective mechanisms of A1-adenosine receptor inhibitors in cardiovascular diseases. METHODS AND RESULTS: Literature references were collected and sorted using relevant keywords and key phrases as search terms in scientific databases such as Web of Science, PubMed and Google Scholar. A1 adenosine receptor regulates free fatty acid metabolism, lipolysis, heart rate, blood pressure, and cardiovascular toxicity. The evidence clearly supporting the therapeutic potency of pharmacological A1 adenosine receptors agonists and antagonists in modulating cardiovascular risk factor parameters and treatment of cardiovascular diseases. CONCLUSION: This review summarizes the protective role of pharmacological A1-adenosine receptor regulators in the pathogenesis of cardiovascular diseases for a better management of cardiovascular diseases.

Vactosertib potently improves anti-tumor properties of 5-FU for colon cancer.

BACKGROUND: Several studies have shown that the TGF-ß signaling pathway plays a critical role in colorectal cancer (CRC) pathogenesis. The aim of the current study is to investigate the therapeutic potential of Vactosertib (EW-7197), a selective inhibitor of TGF-ß receptor type I, either alone or in combination with the standard first-line chemotherapeutic treatment, 5-Fluorouracil (5-FU), in CRC progression in both cellular and animal models. METHODS: Real-Time PCR, Zymography, enzyme-linked immunosorbent assay (ELISA), Hematoxylin and Eosin (H&E) tissue staining, and Flow cytometry techniques were applied to determine the anti-tumor properties of this novel TGF-ß inhibitor in in vitro (CT-26 cell line) and in vivo (inbred BALB/C mice) samples. RESULTS: Our findings showed that Vactosertib decreased cell proliferation and induced spheroid shrinkage. Moreover, this inhibitor suppressed the cell cycle and its administration either alone or in combination with 5-FU induced apoptosis by regulating the expression of p53 and BAX proteins. It also improved 5-FU anti-cancer effects by decreasing the tumor volume and weight, increasing tumor necrosis, and regulating tumor fibrosis and inflammation in an animal model. Vactosertib also enhanced the inhibitory effect of 5-FU on invasive behavior of CRC cells by upregulating the expression of E-cadherin and inhibiting MMP-9 enzymatic activity. CONCLUSION: This study demonstrating the potent anti-tumor effects of Vactosertib against CRC progression. Our results clearly suggest that this inhibitor could be a promising agent reducing CRC tumor progression when administered either alone or in combination with standard treatment in CRC patients.

Influence of Renin-Angiotensin System Inhibitors on the Treatment of Metastatic Renal Cancer.

BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB) are mainly known as anti-hypertensive drugs. Recent evidence suggests their anti-tumor potential against renal cancer. More than one-fourth of patients present with metastasis on their first visit. OBJECTIVE: The purpose of the current study was to examine the potential clinical impact of ACEI/ARB on metastatic renal cell carcinoma (mRCC). METHODS: We searched through several online databases, including Pubmed, Scopus, Web of Science, and Embase, to find clinical studies that have investigated the association between treatment with ACEI/ARB and the survival of patients with mRCC. The hazard ratio (HR) and 95% confidence interval (95% CI) were utilized to assess the strength of the association. RESULTS: A total of 6 studies with a total number of 2,364 patients were found eligible for the final analysis. The HR for the relationship between ACEI/ARB use and overall survival (OS) showed patients undergoing treatment with ACEI/ARB to have higher OS than non-users (HR: 0.664, 95% CI 0.577-0.764, p=0.000). Furthermore, the HR for the relationship between ACEI/ARB use and progression-free survival (PFS) showed patients undergoing treatment with ACEI/ARB to have higher PFS than non-users (HR: 0.734, 95% CI 0.695-0.794, p=0.000). CONCLUSION: The results of this review offer ACEI/ARB as a potential therapeutic option associated with improved survival outcomes in patients receiving anti-vascular endothelial growth factor therapy.

Exploring new therapeutic potentials of curcumin against post-surgical adhesion bands.

BACKGROUND: Adhesion band formation is a common cause of morbidity for patients undergoing surgeries. Anti-inflammatory and anti-fibrotic properties of curcumin, a pharmacologically active component of Curcuma longa, have been investigated in several studies. The aim of this study is to explore the therapeutic potential of curcumin in attenuating post-operative adhesion band (PSAB) formation in both peritoneal and peritendinous surgeries in animal models. METHODS: Bio-mechanical, histological and quantitative evaluation of inflammation, and total fibrosis scores were graded and measured in the presence and absence of phytosomal curcumin. RESULTS: Results showed that phytosomal curcumin significantly decreased severity, length, density and tolerance of mobility of peritendinous adhesions as well as incidence and severity of abdominal fibrotic bands post-surgery. Curcumin may decrease inflammation by attenuating recruitment of inflammatory cells and regulating oxidant/anti-oxidant balance in post-operative tissue samples. Moreover, markedly lower fibrosis scores were obtained in the adhesive tissues of phytosomal curcumin-treated groups which correlated with a significant decrease in quantity, quality and grading of fibers, and collagen deposition in animal models. CONCLUSION: These results suggest that protective effects of phytosomal curcumin against PSAB formation is partially mediated by decreasing inflammation and fibrosis at site of surgery. Further studies are needed to investigate the therapeutic potential of this molecule in preventing PSAB.

The protective effect of curcumin on thrombin-induced hyper-permeability.

Objective: Thrombin is a proinflammatory and pro-coagulant agent which is upregulated in several human diseases. Thrombin has a critical role in promoting cell proliferation and microvascular leakage in malignant cells, resulting in cancer growth and progression. Here, we explored the potential therapeutic value of curcumin on permeability induced by thrombin in mice. Materials and Methods: To assess the activity of curcumin on thrombin-induced vascular permeability mice model, C57BL / 6 mice were randomly divided into four groups: (1) control (2) Thrombin (3) Thrombin + Curcumin and (4) Thrombin + Metformin. Thirty minutes after treatment, Evans blue was injected intravenously through the tail vein to mice. Then, animals were sacrificed and the dye was extracted from the skin tissue by incubation with formamide. Heatmap and correlation map were generated and protein-protein interaction network of the hub genes was drawn by Cytoscape software. Results: Hub DEG expression rate showed that Heat shock protein a1 (Hspa1) family (comprised of HSPa1a, b, and HSPa5), caspase 3, and minichromosome maintenance complex component 2 were overexpressed after treatment with curcumin. Functional modules of curcumin enriched through Enrich gene biological process and revealed positive association of gene expression of apoptosis process with the therapy. Curcumin was also found to reduce leucocyte migration in murine tissues. Additionally, treatment with curcumin resulted in downregulation of heat shock proteins and proinflammatory cytokines such as monocyte chemotactic protein 1, interleukin-6 and chemokine (C-X-C motif) ligand 3. Conclusion: Curcumin inhibited the proinflammatory cytokines and inflammatory HSPs in endothelial cells and reduced thrombin-induced barrier destabilization in vivo.

Mebendazole, an anti-helminth drug, suppresses inflammation, oxidative stress and injury in a mouse model of ulcerative colitis.

Mebendazole (MBZ) is an efficacious anthelmintic with known anti-inflammatory and fibrinolytic properties. In this study, we aimed to explore the protective effects of this FDA-approved drug against DSS-induced colitis in a murine model either alone or in combination with Sulfasalazine (SSZ), a standard therapy for ulcerative colitis. We found that MBZ significantly improved colitis disease activity index as assessed by changes in body weight, degree of stool consistency, rectal bleeding, and prolapse. We also found that MBZ ameliorated the colon histopathological score by attenuating crypt loss, mucosal damage, and inflammation score in colitis tissues. Similarly, DSS-induced colon shortening, colon weight loss, and increase in spleen weight were all abrogated in the presence of MBZ. Moreover, MBZ decreased inflammation, possibly by reducing oxidative stress markers, suppressing inflammatory cell infiltration, and down-regulation of inflammatory genes in colon tissues. Furthermore, MBZ potently reduced fibrosis by decreasing collagen deposition and down-regulating pro-fibrotic genes including Col 1a1 and Col 1a2 in colitis tissue homogenates. In conclusion, our study showed that this broad-spectrum anthelminthic could be repurposed as a novel therapy for ulcerative colitis without any observed side effects, however, regarding the concerns about the potential toxicity of MBZ in UC patients, future experiments on MBZ therapy in other models of UC is needed to completely address the toxicity concerns.

Emerging roles of CD133 in the treatment of gastric cancer, a novel stem cell biomarker and beyond.

Gastric cancer (GC) is an aggressive disease with one of the highest mortality rates in the world. In the early stage, most patients are asymptomatic and early diagnosis is difficult. Recently, cancer stem cells (CSCs) have been highlighted as crucial emerging factors in the initiation or invasiveness of solid tumors. CD133, a CSC marker, is highly expressed in various tumors including gastric cancer. CD133-positive cells showed elevated malignant biological behaviors and CD133 upregulation is related to chemoresistance, cancer relapse, and poor prognosis. CD133 also plays an important role in the progression of tumors and metastasis. This review summarizes the current knowledge of the role of CD133 expression in GC and aims to contribute at identifying promising new strategies for treatment and management of gastric cancer.

Association of a genetic variant in Interleukin-10 gene with increased risk and inflammation associated with cervical cancer.

BACKGROUND: Cervical-cancer is among the most commonly diagnosed cancers in women, and infection with human papillomavirus (HPV) is associated with an increased risk of cervical cancer and altered serum concentrations of inflammatory cytokines. We have explored the association between a genetic variation in the Interleukin-10 (IL-10) gene (rs1800896) and cervical cancer risk and its relationship with tissue Interferon gamma (IFN-γ), Transforming growth factor beta (TGF-ß), Tumor necrosis factor alpha (TNF-α) concentrations in women with cervical cancer. METHODS: A total of 315 women with, or without cervical cancer, were recruited into the study. DNA was extracted from cervical cells, and genotyping was undertaken using Taq-man real-time PCR. The genotype frequency and allele distribution were analyzed together with their association with pathological data. The association of the rs1800896 gene variation with tissue levels of the inflammatory cytokines was also investigated. RESULTS: Our data showed a significant association between the A allele of the rs1800896 gene variant and the presence of cervical cancer. In particular, patients with AG/AA genotypes had an increased risk of cervical cancer with an odds ratio of 1.929 (95% confidence interval [CI]: 0.879-4.23, P < 0.001) in a recessive model, compared with the GG genotype. Also, the tissue concentrations of IFN-γ, TGF-ß, and TNF-α in cervical tissues were significantly higher in women with cervical cancer (P < 0.001) and were associated with the AA genotype. CONCLUSION: We have found an association between the polymorphism rs1800896 in the IL-10 gene and an increased risk of cervical cancer as well as a higher level of tissue inflammatory cytokines. Further investigations are necessary on the value of emerging biomarkers for the risk stratification for the management of cervical cancer patients.

Therapeutic potential of active components of saffron in post-surgical adhesion band formation.

BACKGROUND: Abdominal adhesions are common and often develop after abdominal surgery. There are currently no useful targeted pharmacotherapies for adhesive disease. Saffron and its active constituents, Crocin and Crocetin, are wildly used in traditional medicine for alleviating the severity of inflammatory or malignant disease. PURPOSE: The aim of this study was to investigate the therapeutic potential of the pharmacological active component of saffron in attenuating the formation of post-operative adhesion bands using different administration methods in a murine model. MATERIAL METHOD: saffron extract (100 mg/kg), Crocin (100 mg/kg), and Crocetin (100 mg/kg) were administered intraperitoneally and by gavage in various groups of male Wistar rat post-surgery. Also three groups were first treated intra-peritoneally by saffron extract, Crocin, and Crocetin (100 mg/kg) for 10 days and then had surgery. At the end of the experiments, animals sacrificed for biological assessment. RESULT: A hydro-alcoholic extract of saffron and crocin but not crocetin potently reduced the adhesion band frequency in treatment and pre-treatment groups in the mice given intra-peritoneal (i.p) injections. Following the saffron or crocin administration, histological evaluation and quantitative analysis represented less inflammatory cell infiltration and less collagen composition, compared to control group. Moreover, the oxidative stress was significantly reduced in treatment groups. CONCLUSION: These findings suggest that a hydro-alcoholic extract of saffron or its active compound, crocin, is a potentially novel therapeutic strategy for the prevention of adhesions formation and might be used as beneficial anti-inflammatory or anti-fibrosis agents in clinical trials. TAXONOMY: Abdominal surgeries/post-surgical adhesions.

Metformin inhibits polyphosphate-induced hyper-permeability and inflammation.

Circulating inflammatory factor inorganic polyphosphate (polyP) released from activated platelets could enhance factor XII and bradykinin resulted in increased capillary leakage and vascular permeability. PolyP induce inflammatory responses through mTOR pathway in endothelial cells, which is being reported in several diseases including atherosclerosis, thrombosis, sepsis, and cancer. Systems and molecular biology approaches were used to explore the regulatory role of the AMPK activator, metformin, on polyP-induced hyper-permeability in different organs in three different models of polyP-induced hyper-permeability including local, systemic short- and systemic long-term approaches in murine models. Our results showed that polyP disrupts endothelial barrier integrity in skin, liver, kidney, brain, heart, and lung in all three study models and metformin abrogates the disruptive effect of polyP. We also showed that activation of AMPK signaling pathway, regulation of oxidant/anti-oxidant balance, as well as decrease in inflammatory cell infiltration constitute a set of molecular mechanisms through which metformin elicits it's protective responses against polyP-induced hyper-permeability. These results support the clinical values of AMPK activators including the FDA-approved metformin in attenuating vascular damage in polyP-associated inflammatory diseases.

Rigosertib elicits potent anti-tumor responses in colorectal cancer by inhibiting Ras signaling pathway.

BACKGROUND: The therapeutic potency of Rigosertib (RGS) in the treatment of the myelodysplastic syndrome has been investigated previously, but little is known about its mechanisms of action. METHODS: The present study integrates systems and molecular biology approaches to investigate the mechanisms of the anti-tumor effects of RGS, either alone or in combination with 5-FU in cellular and animal models of colorectal cancer (CRC). RESULTS: The effects of RGS were more pronounced in dedifferentiated CRC cell types, compared to cell types that were epithelial-like. RGS inhibited cell proliferation and cell cycle progression in a cell-type specific manner, and that was dependent on the presence of mutations in KRAS, or its down-stream effectors. RGS increased both early and late apoptosis, by regulating the expression of p53, BAX and MDM2 in tumor model. We also found that RGS induced cell senescence in tumor tissues by increasing ROS generation, and impairing oxidant/anti-oxidant balance. RGS also inhibited angiogenesis and metastatic behavior of CRC cells, by regulating the expression of CD31, E-cadherin, and matrix metalloproteinases-2 and 9. CONCLUSION: Our findings support the therapeutic potential of this potent RAS signaling inhibitor either alone or in combination with standard regimens for the management of patients with CRC.

Angiotensin receptor blocker Losartan inhibits tumor growth of colorectal cancer.

The renin-angiotensin system (RAS) is up-regulated in patients with colorectal cancer (CRC) and is reported to be associated with poor prognosis and chemo-resistance. Here we explored the therapeutic potential of targeting RAS in CRC using Losartan, an angiotensin receptor blocker. An integrative-systems biology approach was used to explore a proteome-level dataset of a gene signature that is modulated by Losartan. The anti-proliferative activity of Losartan was evaluated using 2- and 3-dimensional cell culture models. A xenograft model of colon cancer was used to investigate tumor growth with Losartan alone and in combination with 5-FU followed by histological staining (Hematoxylin & Eosin and Masson trichrome staining), biochemical analyses, gene expression analyses by RT-PCR, western blot/IHC, or MMP Gelatin Zymography studies. Effects on cell cycle and cell death were assessed by flow cytometry. Losartan inhibited cell growth and suppressed cell cycle progression, causing an increase in CRC cells in the G1 phase. Losartan significantly reduced tumor growth and enhanced tumor cell necrosis. An impact on the inflammatory response, including up-regulation of pro-inflammatory cytokines and chemokines in CRC cells are potential mechanisms that could partially explain Losartan's anti-proliferative effects. Moreover, metastasis and angiogenesis were reduced in Losartan-treated mice as observed by inhibited matrix metalloproteinase-2 and -9 activities and decreased tumor vasculature. These data demonstrate the therapeutic potential of combining chemotherapeutic regimens with Losartan to synergistically enhance its activity and target the renin-angiotensin system as a new approach in colorectal cancer treatment.

Inhibition of transforming growth factor-beta by Tranilast reduces tumor growth and ameliorates fibrosis in colorectal cancer.

Transforming Growth Factor-beta (TGF-ß) is dysregulated in colorectal cancer and there is growing evidence that it is associated with a poor prognosis and chemo-resistance in several malignances, including CRC. In this study we have explored the therapeutic potential of targeting TGF-ß using Tranilast in colon cancer. The anti-proliferative activity of Tranilast was evaluated in 2- and 3-dimensional cells. We used a xenograft model of colon cancer to investigate the activity of Tranilast alone or in combination with 5-FU on tumor growth using histological staining and biochemical studies, as well as gene expression analyses using RT-PCR and Western blotting. Tranilast alone or in combination with 5-FU inhibited tumor growth and was associated with a reduction of TGF-ß expression and CD31 positive endothelial cells. Histological evaluation showed that Tranilast increased tumor necrosis and reduced tumor density and angiogenesis. Tranilast increased MDA and ROS production. It was also found that Tranilast reduced total thiol concentration and reduced SOD and catalase activity. Tranilast plus 5-FU was also found to attenuate collagen deposition, reducing tumor fibrosis in tumor xenografts. Our results show that Tranilast, a TGF inhibitor, in combination with 5-FU reduces tumor growth by inhibiting fibrosis and inducting ROS, thus supporting this therapeutic approach in CRC treatment.

Association between genetic variants at 9p21 locus with risk of breast cancer: A systematic review and meta-analysis.

Breast cancer (BC) is the most frequent tumor in women and genetic factors are among the main risk factors contributing to this malignancy. Chromosome 9p21 contains important regulatory non-coding RNAs and is associated with multiple malignancies including BC. The current meta-analysis aimed to investigate the association between genetic variants within the 9p21 locus and risk of breast cancer. A literature search was performed using PubMed, Web of Science, Embase, MEDLINE, Scopus and Clinical key databases. Nine studies containing 23,726 subjects were eligible for the final analysis and specific odds ratios (OR) and confidence intervals (95% CI) were evaluated to assess the strength of the associations. In the pooled analysis, there was an association between the genetic variations in 9p21 locus (CDKN2A/2B) with risk of breast cancer with a standard OR of 1.22 (95% CI: 1.04-1.45, P = 0.016; random-effects model), supporting the significance of this locus as a novel risk factor for breast cancer patients. In conclusion, our results showed that 9p21 region is positively associated with risk of BC and its polymorphisms may be a candidate marker for BC susceptibility.

The diagnostic, prognostic and therapeutic potential of circulating microRNAs in ovarian cancer.

Ovarian cancer (OC) is often diagnosed at an advanced stage because of the late onset of symptoms, and this together with the lack of effective treatments, has meant it is associated with a very high mortality. The aberrant expression of MicroRNA (miRNA) contributes to the initiation and development of human tumors including OC. Several miRNAs are secreted by tumor cells and can be identified in body fluids. Serum miRNAs levels are associated with several clinical conditions, and may be used to predict prognosis and response to treatments in some cancers including OC. This review summarizes the current progresses regarding the potential applications of circulating miRNA as innovative biomarkers in OC.

Intraperitoneal Administration of Telmisartan Prevents Postsurgical Adhesion Band Formation.

BACKGROUND: Angiotensin II receptor blockers (ARBs) have a potential role in reducing inflammation and fibrosis. We have integrated systems and molecular biology approaches to investigate the therapeutic potential of ARBs in preventing postsurgical adhesion band formation. MATERIAL AND METHODS: we have followed the ARRIVE guidelines point by point during experimental studies. Telmisartan (1 and 9 mg/kg), valsartan (1 and 9 mg/kg), and losartan (1 and 10 mg/kg) were administered intraperitoneally in different groups of male albino Wistar rat. After 7 d of treatment, macroscopic evidence and score of fibrotic bands based on scaling methods was performed. Moreover, the anti-inflammatory and antifibrosis effects of telmisartan on reduction of fibrotic bands were investigated by using histopathology, ELISA, and real-time polymerase chain reaction methods. RESULTS: Telmisartan, but not losartan or valsartan, prevented the frequency as well as the stability of adhesion bands. Telmisartan appears to elicit anti-inflammatory responses by attenuating submucosal edema, suppressing proinflammatory cytokines, decreasing proinflammatory cell infiltration, and inhibiting oxidative stress at the site of peritoneal surgery. We also showed that telmisartan prevents fibrotic adhesion band formation by reducing excessive collagen deposition and suppression of profibrotic genes expression at the peritoneum adhesion tissues. CONCLUSIONS: These results support the potential application of telmisartan in preventing postsurgical adhesion band formation by inhibiting key pathologic responses of inflammation and fibrosis in postsurgery patients.

Novel oral transforming growth factor-ß signaling inhibitor potently inhibits postsurgical adhesion band formation.

Here, we have investigated the therapeutic potency of EW-7197, a transforming growth factor-ß type I receptor kinase inhibitor, against postsurgical adhesion band formation. Our results showed that this pharmacological inhibitor prevented the frequency and the stability of adhesion bands in mice model. We have also shown that downregulation of proinflammatory cytokines, reduce submucosal edema, attenuation of proinflammatory cell infiltration, inhibition of oxidative stress, decrease in excessive collagen deposition, and suppression of profibrotic genes at the site of surgery are some of the mechanisms by which EW-7197 elicits its protective responses against adhesion band formation. These results clearly suggest that EW-7197 has novel therapeutic properties against postsurgical adhesion band formation with clinically translational potential of inhibiting key pathological responses of inflammation and fibrosis in postsurgery patients.

Role of the NF-κB signaling pathway in the pathogenesis of colorectal cancer.

The NF-κB signaling pathway is a key regulator of CRC cell proliferation, apoptosis, angiogenesis, inflammation, metastasis, and drug resistance. Over-activation of the NF-κB pathway is a feature of colorectal cancer (CRC). While new combinatorial treatments have improved overall patient outcome; quality of life, cost of care, and patient survival rate have seen little improvement. Suppression of the NF-κB signaling pathway using biological or specific pharmacological inhibitors is a potential therapeutic approach in the treatment of colon cancer. This review summarizes the regulatory role of NF-κB signaling pathway in the pathogenesis of CRC for a better understanding and hence a better management of the disease.

The potential role of regulatory microRNAs of RAS/MAPK signaling pathway in the pathogenesis of colorectal cancer.

Colorectal cancer (CRC) is the leading cause of cancer death worldwide. Dysregulation of RAS/MAPK signaling axis is frequently found in CRC patients. The RAS/MAPK axis regulates cancer cell proliferation, apoptosis, inflammation, migration, and metastasis. Oncogenic or tumor-suppressor microRNAs (miRNAs) for RAS/MAPK signaling play a key role in the pathogenesis of CRC and are considered as novel potential biomarkers for diagnosis and prognosis of human malignancies. This review summarizes the current knowledge of mechanisms of action of RAS/MAPK miRNAs in the development and progression of CRC for a better understanding and hence a better management of this disease.