The LATE score: A novel framework for echocardiographic evaluation of left ventricular filling pressure.

BACKGROUND: The LATE score (LATE: Left Atrial reservoir strain (LASr), Tricuspid regurgitation maximum velocity (TR Vmax), and E/e' average) is a novel framework for echocardiographic assessment of left ventricular filling pressure (LVFP). LATE = 0 indicates normal LVFP. LATE = 1 indicates resting LVFP is borderline elevated, and the patient may be at risk of pathological elevation of LVFP during exertion. LATE ≥2 indicates LVFP is severely elevated. METHODS: The LATE score was derived from reported thresholds of LASr and conventional echocardiographic parameters for predicting LVFP. The LATE score was prospectively evaluated in a cross-sectional study of 63 patients undergoing transthoracic echocardiography immediately prior to cardiac catheterization with invasive assessment of LVFP. Accuracy of the LATE score was compared to 2016 ASE diastology algorithms. RESULTS: Mean patient age was 62.9 ± 13.6 years with 22% female. LATE = 0 in 29 patients, of which 24 (83%) had normal LVFP (mean LVFP 9 mmHg, SD ±3 mmHg). LATE = 1 in 23 patients, of which 11 (48%) had elevated LVFP (mean LVFP 12 mmHg, SD ± 4 mmHg). LATE was ≥2 in 11 patients, all of which had elevated LVFP (100%) (mean LVFP 16 mmHg, SD ±3 mmHg). The LATE score showed greater agreement with invasive assessment than the 2016 algorithms (LATE kappa = 0.73, 2016 kappa = 0.37). CONCLUSIONS: The LATE score is a simple and effective tool for evaluation of LVFP that is more accurate than the 2016 algorithms. The LATE score provides insight beyond binary classification of normal versus elevated LVFP.

Implications of estrogen and its receptors in colorectal carcinoma.

Estrogens have been implicated in the pathogenesis of various cancer types, including colorectal carcinoma (CRC). Estrogen receptors such as ERα and ERß activate intracellular signaling cascades followed by binding to estrogen, resulting in important changes in cellular behaviors. The nuclear estrogen receptors, i.e. ERß and ERα are responsible for the genomic actions of estrogens, whereas the other receptor, such as G protein-coupled estrogen receptor (GPER) regulates rapid non-genomic actions, which lead to secondary gene expression changes in cells. ERß, the predominant estrogen receptor expressed in both normal and non-malignant colonic epithelium, has protective roles in colon carcinogenesis. ERß may exert the anti-tumor effect through selective activation of pro-apoptotic signaling, increasing DNA repair, inhibiting expression of oncogenes, regulating cell cycle progression, and also by changing the micro-RNA pool and DNA-methylation. Thus, a better understanding of the underlying mechanisms of estrogen and its receptors in CRC pathogenesis could provide a new horizon for effective therapeutic development. Furthermore, using synthetic or natural compounds as ER agonists may induce estrogen-mediated anti-cancer activities against colon cancer. In this study, we report the most recent pre-clinical and experimental evidences related to ERs in CRC development. Also, we reviewed the actions of naturally occurring and synthetic compounds, which have a protective role against CRC development by acting as ER agonist.

Left atrial reservoir strain provides incremental value to left atrial volume index for evaluation of left ventricular filling pressure.

BACKGROUND: Left atrial analysis is employed in diastolic assessment with left atrial volume index (LAVI) incorporated in the 2016 ASE/EACVI diastology guideline algorithm. LAVI has sub-optimal correlation with invasive left ventricular filling pressure (LVFP) and incorporation of left atrial reservoir strain (LASr) may improve diastolic assessment. METHODS: A cross-sectional prospective study of 139 patients was undertaken with all patients undergoing transthoracic echocardiography immediately prior to cardiac catheterization with invasive evaluation of LVFP. LASr by speckle tracking echocardiography and conventional echocardiographic parameters were assessed in relation to invasive LVFP. Modification of the 2016 guideline algorithm was performed with incorporation of LASr in place of LAVI (LASr ≤23% indicating elevated LVFP). Accuracy of the modified and conventional algorithm were assessed for predicting invasive LVFP. RESULTS: The mean age was 63±12 years with 27% female. LASr demonstrated superior correlation and receiver operator characteristic for predicting LVFP than LAVI (LASr: r -.46 (p < 0.01), AUC: .82 vs LAVI: r .19 (p 0.02), AUC: .66). LASr of ≤23% was the optimal cut-off for discriminating elevated LVFP (sensitivity 80%, specificity 77%). Modification of the 2016 algorithm with incorporation of LASr in place of LAVI reclassified 12% of the patient cohort and improved concordance of echocardiographic and invasive LVFP assessment (modified algorithm κ .47 vs 2016 algorithm κ: .33). No patients were incorrectly reclassified by modified algorithm assessment. CONCLUSIONS: LASr better predicts invasive LVFP than LAVI. Modification of the 2016 guideline algorithm with incorporation of LASr in place of LAVI improves accuracy of echocardiographic assessment of LVFP.

Significance of serglycin and its binding partners in autocrine promotion of metastasis in esophageal cancer.

Rationale: Little is known about the roles of proteoglycans in esophageal cancer. This study aims to investigate the roles and mechanisms of serglycin (SRGN) proteoglycan in promoting metastasis of esophageal squamous cell carcinoma (ESCC). Methods: Reverse phase protein array analysis was used to identify activated signaling pathways in SRGN-overexpressing cells. Chemokine array was used to identify differentially secreted factors from SRGN-overexpressing cells. Binding between SRGN and potential interacting partners was evaluated using proximity ligation assay and co-immunoprecipitation. The glycosaminoglycan (GAG) chains of SRGN were characterized using fluorophore-assisted carbohydrate electrophoresis. Tissue microarray and serum samples were used to determine the correlation of SRGN expression with clinicopathological parameters and patient survival. Results: In vitro and in vivo experiments showed that SRGN promoted invasion and metastasis in ESCC via activating ERK pathway, stabilizing c-Myc and upregulating the secretion of matrix metalloproteinases. SRGN-knockdown suppressed tumorigenic hallmarks. These SRGN-elicited functions were carried out in an autocrine manner by inducing the secretion of midkine (MDK), which was further identified as a novel binding partner of SRGN for the formation of a SRGN/MDK/CD44 complex. In addition, SRGN interacted with MDK and matrix metalloproteinase 2 in ESCC via its GAG chains, which were mainly decorated with chondroitin sulfate comprising of ∆di-4S and ∆di-6S CS. Clinically, high expression of serum SRGN in serum of patients with ESCC was an independent prognostic marker for poor survival. Conclusions: This study provides the first evidence that elevated serum SRGN has prognostic significance in patients with ESCC, and sheds light on the molecular mechanism by which elevated circulating SRGN in cancer patients might promote cancer progression.

Plasticity of Cancer Stem Cell: Origin and Role in Disease Progression and Therapy Resistance.

In embryonic development and throughout life, there are some cells can exhibit phenotypic plasticity. Phenotypic plasticity is the ability of cells to differentiate into multiple lineages. In normal development, plasticity is highly regulated whereas cancer cells re-activate this dynamic ability for their own progression. The re-activation of these mechanisms enables cancer cells to acquire a cancer stem cell (CSC) phenotype- a subpopulation of cells with increased ability to survive in a hostile environment and resist therapeutic insults. There are several contributors fuel CSC plasticity in different stages of disease progression such as a complex network of tumour stroma, epidermal microenvironment and different sub-compartments within tumour. These factors play a key role in the transformation of tumour cells from a stable condition to a progressive state. In addition, flexibility in the metabolic state of CSCs helps in disease progression. Moreover, epigenetic changes such as chromatin, DNA methylation could stimulate the phenotypic change of CSCs. Development of resistance to therapy due to highly plastic behaviour of CSCs is a major cause of treatment failure in cancers. However, recent studies explored that plasticity can also expose the weaknesses in CSCs, thereby could be utilized for future therapeutic development. Therefore, in this review, we discuss how cancer cells acquire the plasticity, especially the role of the normal developmental process, tumour microenvironment, and epigenetic changes in the development of plasticity. We further highlight the therapeutic resistance property of CSCs attributed by plasticity. Also, outline some potential therapeutic options against plasticity of CSCs. Graphical Abstract .

Kaempferia rotunda tuberous rhizome lectin induces apoptosis and growth inhibition of colon cancer cells in vitro.

Kaempferia rotunda Linn. is a plant of ginger family and has many medicinal values in traditional applications, including as antimicrobial and anticancer agents. The present study aims to examine the anticancer activity of Kaempferia rotunda tuberous rhizome lectin (KRL, MW 29 ±â€¯1.0 kDa) against colon cancer cells SW480 and SW48. KRL inhibited 67% and 59% of SW480 and SW48 cells growth respectively at the concentration of 1.0 mg/ml. The cells growth inhibition was a dose dependent manner. KRL treatments notably inhibited the colony formation capacity of the cancer cells. The surviving fractions of SW480 and SW48 cells treated with KRL significantly (p < 0.001) reduced compared to that of control cells. Significant increment of the apoptotic cells were noted following by G0/G1 or G2/M cell cycle arrest in KRL treated SW480 and SW48 cells, respectively. Modulation of PARP1, p53, p21, Bax and Bcl2 proteins expression was observed in treated cells in comparison to that of untreated cells. Furthermore, activation of caspase-3 and caspase-9 was noted in KRL treated cells and caspase-3 and caspase-9 inhibitors pre-treated cells were shown insensitive to KRL treatment. The results implied that KRL prevents SW480 and SW48 cells proliferation by the induction of apoptosis in the mitochondrial intrinsic pathway.

Protein interactions of FAM134B with EB1 and APC/beta-catenin in vitro in colon carcinoma.

FAM134B is an autophagy regulator of endoplasmic reticulum and acts as a cancer suppressor in colon cancer. However, the molecular signaling pathways by which FAM134B interacts within colon carcinogenesis is still unknown. Herein, this study aims to determine the interacting partners of FAM134B for the first time in colon cancer and to explore the precise location of FAM134B in cancer signalling pathways. Liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) followed by anti-FAM134B co-immune precipitation of FAM134B interacting complex was used to identify the potential interactors of FAM134B in colon cancer cells. Western blot and confocal microscopic analysis were used to validate the physical interactions of FAM134B with the interactors. Lentiviral shRNA mediated silencing of FAM134B was used to examine the modulation of FAM134B interactors in cells. We have identified 29 novel binding partners, including CAP1, RPS28, FTH1, KDELR2, MAP4, EB1, PSMD6, PPIB/CYPB etc. Subsequent immunoassays confirmed the direct physical interactions of FAM134B with CAP1, EB1, CYPB, and KDELR2 in colon cancer cells. Exogenous suppression of FAM134B has led to significant upregulation of EB1 as well as reduction of KDELR2 expression. It was noted that overexpression of EB1 promotes WNT/ß-catenin signaling pathways via inactivating tumor suppressor APC followed by activating ß-catenin in colorectal carcinogenesis. This study has first time reported the gene signaling networks with which FAM134B interacts and noted that FAM134B is involved in the regulation of WNT/ß-catenin pathway by EB1-mediated modulating of APC in colon cancer cells.

Evaluation of multidisciplinary strategies and traditional approaches in teaching pathology in medical students.

This study aims to evaluate the impact on the implementation of multiple strategies to improve medical student's pathology learning experience. In two consecutive years, medical students after a whole year of enrolling in pathology teaching, were invited to complete questionnaires rating and commenting on the personal learning experience of multiple teaching resources delivered in pathology. In both years, the overall score was high (mean score = 4.57 ± 0.63 /5) for the newly introduced sessions, namely histology lectures, clinical integrations and virtual microscopy pre-practical sessions. However, this was only marginally different from that of traditional practical (mean = 4.37 ± 0.68/5) and pathology lecture sessions (mean = 4.42 ± 0.61 /5). In addition, 53% positive correlation was noted for the overall responses between virtual microscopy guided pathology modules and practical sessions indicating the benefit of virtual microscopy in better preparing students for these sessions (P < 0.001). Qualitative comments suggested that the virtual microscopy sessions along with clinical scenario based learning were extremely useful for students' learning in pathology. To conclude, a multidisciplinary approach by clinical integration and flexibility in the mode of delivery by the use of virtual microscopy has the potential to better engage students to the learning of pathology.

Pea lectin inhibits cell growth by inducing apoptosis in SW480 and SW48 cell lines.

Globally, colorectal cancer is the third most common type of malignant tumor, after lung and breast. Here anticancer property of pea lectin was evaluated against colorectal cancer cell lines SW480 and SW48. The cells were treated with different doses of lectin for 3 days in vitro and the inhibitory effects were found in a dose dependent manner. At the high dose(1.0 mg/ml) 62% and 63% cell growth inhibitions were observed for SW48 and SW480 cell lines, respectively. Cell growth inhibition was further studied by colony formation of the cell lines and the numbers of colonies in SW480+pea lectin and SW48+pea lectin cells were noted significantly lower in comparison to that of control cells. Cell morphological study revealed that pea lectin induced apoptosis both in SW48 and SW480 cell lines, which was further confirmed by caspase inhibitors. Involvement of intrinsic mitochondrial pathway in the apoptosis progression was confirmed by caspase inhibitors and increased of caspase-3 & -9 proteins expressions. Expression levels of p53 and p21 protein were also increased significantly in both cell lines with the decreased of PARP1 protein expression. G2/M and G0/G1 cell cycle arrested was noted in SW48 and SW480 cell lines, respectively, after treatment with pea lectin.

Role of miR-193a in Cancer: Complexity and Factors Control the Pattern of its Expression.

BACKGROUND: There is emerging data suggesting that the non-coding RNA (microRNA 193a or miR-193a) plays key roles in different types of cancers. OBJECTIVE: This review aims to investigate the functional significance of miR-193a in different cancers according to the information of literature. METHOD: All the literature concerning miR-193a in cancer in PubMed are analysed. RESULTS: Several studies proved the association of miR-193a expression patterns with cancer's stages, grades, response to the chemotherapy and even patient survival. Also, miR-193a can be used to differentiate some types of cancer. In cancer, miR-193a can act as a tumour suppressor gene or as an oncogene. Till now, several genetic factors (MAX, RXR α, XB130, P63, P73, AEG-1, HIFs, EGFR, Drosha, DGCR8, Dicer) and epigenetic factors (DNA methylation and long non-coding RNAs) were predicted to control miR-193a expression. They have fundamental effects on its biological behaviour in different types of cancers. CONCLUSION: miR-193a has significant roles in cancer and can be targeted in the future for cancer therapy by better understanding of the factors that control its biological behaviour.

MiR-142-5p act as an oncogenic microRNA in colorectal cancer: Clinicopathological and functional insights.

OBJECTIVES: miR-142-5p was noted aberrantly expressed and plays important roles in different pathophysiological conditions in human. The present study aims to examine the expression of miR-142-5p and its association with clinicopathological factors in a large cohort of patients with colorectal cancer. In addition, the cellular effects of miR-142-5p and its interacting targets in colon cancer cells were investigated. METHODS: Expression of miR-142-5p in colorectal cancer tissues (n=125) and colon cancer cell lines were analysed using real-time polymerase chain reaction. In vitro assays (cell proliferation, wound healing and colony formation) were used to study the miR-142-5p induced cellular effects. Western blots were used to examine the modulation of FAM134B, KRAS, EPAS1 and KLF6 proteins expression followed by miR-142-5p expression-manipulation. RESULTS: Significant high expression of miR-142-5p was noted in cancer tissues and cells when compared to the controls (p<0.001). Overexpression of miR-142-5p in patients with colorectal cancer was common (72%; 90/125). miR-142-5p overexpression was associated with cancer in the proximal colorectum and with B-raf positive patients (p=0.05). Exogenous overexpression of miR-142-5p resulted in significantly increased cell proliferation, colony formation, and wound healing capacities, whereas inhibition of endogenous miR-142-5p led reduced cancer growth properties. The cellular effects of miR-142-5p were mediated by the modulation of tumour suppressor KLF6 expression, as the expression of miR-142-5p and KLF6 protein are inversely correlated in colon cancer cells. CONCLUSION: High miR-142-5p expression was associated with the biological aggressiveness of cancer. Thus, suppression of miR-142-5p could be a therapeutic strategy for patients with colorectal cancers.

MicroRNA-186-5p overexpression modulates colon cancer growth by repressing the expression of the FAM134B tumour inhibitor.

OBJECTIVES: The role and underlying mechanism of miR-186-5p in colorectal cancer remain unknown. The present study aims to examine the various cellular effects of miR-186-5p in the carcinogenesis of colorectal cancer. Also, the interacting targets and association of clinicopathological factors with miR-186-5p expression in patients with colorectal cancer were analysed. METHODS: The miR-186-5p expression levels in colorectal cancer tissues (n=126) and colon cancer cell lines (n=3) were analysed by real-time PCR. Matched non-neoplastic colorectal tissues and a non-neoplastic colonic epithelial cell line were used as controls. Various in vitro assays such as cell proliferation, wound healing and colony formation assays were performed to examine the miR-186-5p specific cellular effects. Western blots and immunohistochemistry analysis were performed to examine the modulation of FAM134B, PARP9 and KLF7 proteins expression. RESULTS: Significant high expression of miR-186-5p was noted in cancer tissues (p< 0.001) and cell lines (p<0.05) when compared to control tissues and cells. The majority of the patients with colorectal cancer (88/126) had shown overexpression of miR-186-5p. This miR-186-5p overexpression was predominantly noted with in cancer with distant metastasis (p=0.001), lymphovascular permeation (p=0.037), microsatellite instability (MSI) stable (p=0.015), in distal colorectum (p=0.043) and with associated adenomas (p=0.047). Overexpression of miR-186-5p resulted in increased cell proliferation, colony formation, wound healing capacities and induced alteration of cell cycle kinetics in colon cancer cells. On the other hand, inhibition of endogenous miR-186-5p reduced the cancer growth properties. miR-186-5p overexpression reduced FAM134B expression significantly in the cancer cells (p<0.01). Also, FAM134B and miR-186-5p expressions are inversely correlated in colorectal cancer tissues and cells. CONCLUSION: The miR-186-5p expression promotes colorectal cancer pathogenesis by regulating tumour suppressor FAM134B. Reduced cancer cells growth followed by inhibition of miR-186-5p highlights the potential of miR-186-5p inhibitor as a novel strategy for targeting colorectal cancer initiation and progression.

Novel FAM134B mutations and their clinicopathological significance in colorectal cancer.

FAM134B is a putative tumour suppressor gene and no mutations in FAM134B have been reported in colorectal cancer (CRC) to date. This study aims to identify FAM134B mutation sites and the clinicopathological significance of the gene in patients with CRC. Eighty-eight colorectal cancers were studied for FAM134B mutations by Sanger sequencing. The mutations in these cancers were then tested for correlations with the clinical and pathological parameters of the studied cancers. In addition, mRNA and protein expression of FAM134B in colorectal cancers was examined by polymerase chain reaction, Western blots, and immunofluorescence analysis. FAM134B mutation was noted in 46.5% (41/88) of patients with CRC. Thirty-one novel potentially pathogenic mutations were noted in coding and intronic regions of FAM134B in CRC, the majority of which were single-nucleotide substitutions. Of the 31 mutations, eight novel frameshift mutations showed potential to cause non-sense-mediated mRNA decay (NMD) in computational analysis. In addition, FAM134B mutations were associated with various clinical and pathological variables, including sex of the patients, presence of metachronous cancer, size, T staging, presence of distant metastases, and positivity of microsatellite instability (MSI) in the cancer (p < 0.05). FAM134B mRNA and protein expression was decreased in FAM134B mutated cancers. To conclude, FAM134B mutation is common in colorectal cancer. The association of the mutation of this gene with adverse clinical and pathological parameters is congruent with the tumour suppressive properties of the gene.

Expression pattern of miR-451 and its target MIF (macrophage migration inhibitory factor) in colorectal cancer.

AIMS: To investigate the expression pattern of microRNA-451 (miR-451) in patients with colorectal carcinoma and correlate with the expression of its target gene MIF (macrophage migration inhibitory factor). METHODS: Matched cancer and non-cancer fresh frozen tissues were prospectively collected from 70 patients (35 men and 35 women) who underwent resection of colorectal adenocarcinoma. These tissues collected were extracted for miR and complementary DNA conversion. Then, miR-451 expressions in these tissues were measured by quantitative real-time PCR. The expression was correlated with clinical and pathological parameters of these patients. In addition, paraffin blocks of 10 colorectal carcinomas with lowest expression of miR-451 were used for the study of MIF protein expression by immunohistochemistry. RESULTS: miR-451 was downregulated in majority of the colorectal cancer tissues when compared with their matched normal tissues (84.3%, n=59/70). Downregulation of miR-451 correlates significantly with presence of coexisting adenoma (91.4%, p=0.025). In addition, persistence of cancer or cancer recurrence after surgery showed significant correlation with downregulation of miR-451 (80% vs 0%; p=0.028). There is no significant correlation between miR-451 expression and age, gender of the patients as well as size, grades, pathological stages, presence of lymphovascular permeation, perineural invasion and microsatellite instability status of the colorectal carcinoma (p>0.05). Majority of the cases (80%) with low expression of miR-451 showed high levels of MIF protein expression confirming the inverse relationship between miR-451 and MIF expressions. CONCLUSIONS: The results showed that miR-451 could play a role in development and progression of colorectal cancer and likely by targeting MIF.

Updates on the genetics and the clinical impacts on phaeochromocytoma and paraganglioma in the new era.

Genetic mutations of phaeochromocytoma (PCC) and paraganglioma (PGL) are mainly classified into two major clusters. Cluster 1 mutations are involved with the pseudo hypoxic pathway and comprised of PHD2, VHL, SDHx, IDH, HIF2A, MDH2 and FH mutated PCC/PGL. Cluster 2 mutations are associated with abnormal activation of kinase signalling pathways and included mutations of RET, NF1, KIF1Bß, MAX and TMEM127. In addition, VHL, SDHx (cluster 1 genes) and RET, NF1 (cluster 2 genes) germline mutations are involved in the neuronal precursor cell pathway in the pathogeneses of PCC/PGL. Also, GDNF, H-ras, K-ras, GNAS, CDKN2A (p16), p53, BAP1, BRCA1&2, ATRX and KMT2D mutations have roles in the development of PCC/PGLs. Overall, known genetic mutations account for the pathogenesis of approximately 60% of PCC/PGLs. Genetic mutations, pathological parameters and biochemical markers are used for better prediction of the outcome of patients with this group of tumours. Immunohistochemistry and gene sequencing can ensure a more effective detection, prediction of malignant potential and treatment of PCC/PCLs.

"Googling" for Cancer: An Infodemiological Assessment of Online Search Interests in Australia, Canada, New Zealand, the United Kingdom, and the United States.

BACKGROUND: The infodemiological analysis of queries from search engines to shed light on the status of various noncommunicable diseases has gained increasing popularity in recent years. OBJECTIVE: The aim of the study was to determine the international perspective on the distribution of information seeking in Google regarding "cancer" in major English-speaking countries. METHODS: We used Google Trends service to assess people's interest in searching about "Cancer" classified as "Disease," from January 2004 to December 2015 in Australia, Canada, New Zealand, the United Kingdom, and the United States. Then, we evaluated top cities and their relative search volumes (SVs) and country-specific "Top searches" and "Rising searches." We also evaluated the cross-country correlations of SVs for cancer, as well as rank correlations of SVs from 2010 to 2014 with the incidence of cancer in 2012 in the abovementioned countries. RESULTS: From 2004 to 2015, the United States (relative SV [from 100]: 63), Canada (62), and Australia (61) were the top countries searching for cancer in Google, followed by New Zealand (54) and the United Kingdom (48). There was a consistent seasonality pattern in searching for cancer in the United States, Canada, Australia, and New Zealand. Baltimore (United States), St John's (Canada), Sydney (Australia), Otaika (New Zealand), and Saint Albans (United Kingdom) had the highest search interest in their corresponding countries. "Breast cancer" was the cancer entity that consistently appeared high in the list of top searches in all 5 countries. The "Rising searches" were "pancreatic cancer" in Canada and "ovarian cancer" in New Zealand. Cross-correlation of SVs was strong between the United States, Canada, and Australia (>.70, P<.01). CONCLUSIONS: Cancer maintained its popularity as a search term for people in the United States, Canada, and Australia, comparably higher than New Zealand and the United Kingdom. The increased interest in searching for keywords related to cancer shows the possible effectiveness of awareness campaigns in increasing societal demand for health information on the Web, to be met in community-wide communication or awareness interventions.

Translational potential of cancer stem cells: A review of the detection of cancer stem cells and their roles in cancer recurrence and cancer treatment.

Cancer stem cells (CSCs) are a subpopulation of cancer cells with many clinical implications in most cancer types. One important clinical implication of CSCs is their role in cancer metastases, as reflected by their ability to initiate and drive micro and macro-metastases. The other important contributing factor for CSCs in cancer management is their function in causing treatment resistance and recurrence in cancer via their activation of different signalling pathways such as Notch, Wnt/ß-catenin, TGF-ß, Hedgehog, PI3K/Akt/mTOR and JAK/STAT pathways. Thus, many different therapeutic approaches are being tested for prevention and treatment of cancer recurrence. These may include treatment strategies targeting altered genetic signalling pathways by blocking specific cell surface molecules, altering the cancer microenvironments that nurture cancer stem cells, inducing differentiation of CSCs, immunotherapy based on CSCs associated antigens, exploiting metabolites to kill CSCs, and designing small interfering RNA/DNA molecules that especially target CSCs. Because of the huge potential of these approaches to improve cancer management, it is important to identify and isolate cancer stem cells for precise study and application of prior the research on their role in cancer. Commonly used methodologies for detection and isolation of CSCs include functional, image-based, molecular, cytological sorting and filtration approaches, the use of different surface markers and xenotransplantation. Overall, given their significance in cancer biology, refining the isolation and targeting of CSCs will play an important role in future management of cancer.

Cancer stem cells in oesophageal squamous cell carcinoma: Identification, prognostic and treatment perspectives.

Cancer stem cells (CSCs) are a vital subpopulation of cells to target for the treatment of cancers. In oesophageal squamous cell carcinoma (ESCC), there are several markers such as CD44, ALDH, Pygo2, MAML1, Twist1, Musashi1, Side population (SP), CD271 and CD90 that have been proposed to identify the cancer stem cells in individual cancer masses. It has also been demonstrated that stem cell markers like ALDH1, HIWI, Oct3/4, ABCG2, SOX2, SALL4, BMI-1, NANOG, CD133 and podoplanin are associated with patient's prognosis, pathological stages, cancer recurrence and therapy resistance. Finding new cancer stem cell targets or designing drugs to manipulate the known molecular targets in CSCs could be useful for improvements in clinical outcomes of the disease. To conclude, data suggest that CSCs in oesophageal squamous cell carcinoma are related to resistance to therapy and poor prognosis of patients with ESCC. Therefore, innovative insights into CSC biology and CSC-targeted therapies will help to achieve more effective management of patients with oesophageal squamous cell carcinoma.

Cancer stem cell: fundamental experimental pathological concepts and updates.

Cancer stem cells (CSCs) are a subset of cancer cells which play a key role in predicting the biological aggressiveness of cancer due to its ability of self-renewal and multi-lineage differentiation (stemness). The CSC model is a dynamic one with a functional subpopulation of cancer cells rather than a stable cell population responsible for tumour regeneration. Hypotheses regarding the origins of CSCs include (1) malignant transformation of normal stem cells; (2) mature cancer cell de-differentiation with epithelial-mesenchymal transition and (3) induced pluripotent cancer cells. Surprisingly, the cancer stem cell hypothesis originated in the late nineteenth century and the existence of haematopoietic stem cells was demonstrated a century later, demonstrating that the concept was possible. In the last decade, CSCs have been identified and isolated in different cancers. The hallmark traits of CSCs include their heterogeneity, interaction with microenvironments and plasticity. Understanding these basic concepts of CSCs is important for translational applications using CSCs in the management of patients with cancer.