Deubiquitinating enzyme MINDY1 is an independent risk factor for the maintenance of stemness and poor prognosis in liver cancer cells / 中华肝脏病杂志

Objective: To explore the key deubiquitinating enzymes that maintain the stemness of liver cancer stem cells and provide new ideas for targeted liver cancer therapy. Methods: The high-throughput CRISPR screening technology was used to screen the deubiquitinating enzymes that maintain the stemness of liver cancer stem cells. RT-qPCR and Western blot were used to analyze gene expression levels. Stemness of liver cancer cells was detected by spheroid-formation and soft agar colony formation assays. Tumor growth in nude mice was detected by subcutaneous tumor-bearing experiments. Bioinformatics and clinical samples were examined for the clinical significance of target genes. Results: MINDY1 was highly expressed in liver cancer stem cells. The expression of stem markers, the self-renewal ability of cells, and the growth of transplanted tumors were significantly reduced and inhibited after knocking out MINDY1, and its mechanism of action may be related to the regulation of the Wnt signaling pathway. The expression level of MINDY1 was higher in liver cancer tissues than that in adjacent tumors, which was closely related to tumor progression, and its high expression was an independent risk factor for a poor prognosis of liver cancer. Conclusion: The deubiquitinating enzyme MINDY1 promotes stemness in liver cancer cells and is one of the independent predictors of poor prognosis in liver cancer.

LIMP-2 enhances cancer stem-like cell properties by promoting autophagy-induced GSK3β degradation in head and neck squamous cell carcinoma / 国际口腔科学杂志·英文版

Cancer stem cell-like cells (CSCs) play an integral role in the heterogeneity, metastasis, and treatment resistance of head and neck squamous cell carcinoma (HNSCC) due to their high tumor initiation capacity and plasticity. Here, we identified a candidate gene named LIMP-2 as a novel therapeutic target regulating HNSCC progression and CSC properties. The high expression of LIMP-2 in HNSCC patients suggested a poor prognosis and potential immunotherapy resistance. Functionally, LIMP-2 can facilitate autolysosome formation to promote autophagic flux. LIMP-2 knockdown inhibits autophagic flux and reduces the tumorigenic ability of HNSCC. Further mechanistic studies suggest that enhanced autophagy helps HNSCC maintain stemness and promotes degradation of GSK3β, which in turn facilitates nuclear translocation of β-catenin and transcription of downstream target genes. In conclusion, this study reveals LIMP-2 as a novel prospective therapeutic target for HNSCC and provides evidence for a link between autophagy, CSC, and immunotherapy resistance.

Extracellular vesicle-carried GTF2I from mesenchymal stem cells promotes the expression of tumor-suppressive FAT1 and inhibits stemness maintenance in thyroid carcinoma / 医学前沿

Through bioinformatics predictions, we identified that GTF2I and FAT1 were downregulated in thyroid carcinoma (TC). Further, Pearson's correlation coefficient revealed a positive correlation between GTF2I expression and FAT1 expression. Therefore, we selected them for this present study, where the effects of bone marrow mesenchymal stem cell-derived EVs (BMSDs-EVs) enriched with GTF2I were evaluated on the epithelial-to-mesenchymal transition (EMT) and stemness maintenance in TC. The under-expression of GTF2I and FAT1 was validated in TC cell lines. Ectopically expressed GTF2I and FAT1 were found to augment malignant phenotypes of TC cells, EMT, and stemness maintenance. Mechanistic studies revealed that GTF2I bound to the promoter region of FAT1 and consequently upregulated its expression. MSC-EVs could shuttle GTF2I into TPC-1 cells, where GTF2I inhibited TC malignant phenotypes, EMT, and stemness maintenance by increasing the expression of FAT1 and facilitating the FAT1-mediated CDK4/FOXM1 downregulation. In vivo experiments confirmed that silencing of GTF2I accelerated tumor growth in nude mice. Taken together, our work suggests that GTF2I transferred by MSC-EVs confer antioncogenic effects through the FAT1/CDK4/FOXM1 axis and may be used as a promising biomarker for TC treatment.

Lung Cancer Stem-like Cells and Drug Resistance / 中国肺癌杂志

Lung cancer remains the leading cause of cancer-related death world-wide. Therapy resistance and relapse are considered major reasons contributing to the poor survival rates of lung cancer. Accumulated evidences have demonstrated that a small subpopulation of stem-like cells existed within lung cancer tissues and cell lines, possessing the abilities of self-renewal, multipotent differentiation and unlimited proliferation. These lung cancer stem-like cells (LCSCs) can generate tumors with high effeciency in vivo, survive cytotoxic therapies, and eventually lead to therapy resistance and recurrence. In this review, we would like to present recent knowledges on LCSCs, including the origins where they come from, the molecular features to identify them, and key mechanisms for them to survive and develop resistance, in order to provide a better view for targeting them in future clinic.
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The regulatory pathways leading to stem-like cells underlie prostate cancer progression / 亚洲男科学杂志(英文版)

Prostate cancer (PCa) is the most common cause of malignancy in males and the third leading cause of cancer mortality in the United States. The standard care for primary PCa with local invasive disease mainly is surgery and radiation. For patients with distant metastases, androgen deprivation therapy (ADT) is a gold standard. Regardless of a favorable outcome of ADT, patients inevitably relapse to an end-stage castration-resistant prostate cancer (CRPC) leading to mortality. Therefore, revealing the mechanism and identifying cellular components driving aggressive PCa is critical for prognosis and therapeutic intervention. Cancer stem cell (CSC) phenotypes characterized as poor differentiation, cancer initiation with self-renewal capabilities, and therapeutic resistance are proposed to contribute to the onset of CRPC. In this review, we discuss the role of CSC in CRPC with the evidence of CSC phenotypes and the possible underlying mechanisms.

Oral cancer stem cells - properties and consequences

Abstract Research on cancer stem cells (CSCs) has greatly increased in the field of medicine and pathology; however, some conceptual misunderstandings are still present among the public as well as within the general scientific community that is not yet familiar with the subject. The very first problem is the misinterpretation of CSCs as a synonym of their normal counterparts, the well-known stem cells (SCs). Particularly in Dentistry, another common mistake is the misinterpretation of oral CSCs as normal tooth-derived SCs. The present review aims to clarify important concepts related to normal SCs and CSCs, as well as discuss the relevance of CSCs to the development, metastasis and therapy resistance of oral squamous cell carcinoma.

Isolation of breast cancer stem cell from MDA-MB231 cell line using vincristine / Aislamiento de células madre de cáncer de mama de la línea celular MDA-MB231 utilizando vincristina

Cancer has been considered as a stem cell disease. Suspension culture combined with anti-cancer drugs has recently been proposed for isolation of cancer stem cells (CSCs). In the current study, Vincristine as an anti-cancer drug combined with suspension culture was used for isolation and purification of CSCs from human breast cancer cell line (MDA-MB231). The cells were treated with different concentrations of vincristine (0, 2, 4, 6 and 8 ng/ml). Stem cells were identified with the expression of OCT4, nanog, SOX2 and nucleostemin genes by RT-PCR. Mammosphere forming unit was measured upon suspension culture containing EGF, bFGF, LIF, B27, insulin and BSA. The isolated mammospheres were investigated for CD44 expression. Results showed that 4 ng/ml of vincristine for 72 hours could be utilized as the best and most reliable dose which eliminates around 80 % of non-cancer stem cells with no destructive effect on CSCs' viability (P> 0.05). RT-PCR demonstrated that drug treated cells expressed OCT4, nanog, SOX2 and nucleostemin. Mammosphere formation unit of cells pretreated with vincristine was significantly higher than unpretreated ones (P>0.05). Immunofluorescence staining for CD44 depicted high expression of CSC marker among the isolated mammospheres. Vincristine combined with suspension culture can be considered as an appropriate method to isolate CSC.

El cáncer ha sido considerado como una enfermedad de células madre. Recientemente se ha propuesto cultivo en suspensión en combinación con medicamentos contra el cáncer para aislamiento de las células madre del cáncer (CMC). En este estudio se utilizó la vincristina como fármaco anticanceroso combinado con cultivo en suspensión para el aislamiento y purificación de las células madre cancerosas, de la línea celular de cáncer de mama humano (MDA-MB231). Las células se trataron con diferentes concentraciones de vincristina (0, 2, 4, 6 y 8 ng/ml). Las células madre se identificaron mediante la expresión de los genes OCT4, Nanog, SOX2 y nucleostemin por RT-PCR. La unidad de formación mammosphere se midió a través de cultivo en suspensión que contenía EGF, bFGF, LIF, B27, insulina y BSA. Los mammospheres aislados fueron estudiados para la expresión de CD44. Los resultados mostraron que 4 ng/ml de vincristina durante 72 horas podrían ser utilizados como la mejor y más fiable dosis que permite eliminar alrededor del 80 % de las células madre no cancerosas, sin causar un efecto destructivo sobre la viabilidad de las CMC (P> 0,05). La RT-PCR mostró que en las células tratadas con él fármaco hubo expresión de los genes OCT4, Nanog, SOX2 y nucleostemin. La unidad de formación de las células pretratadas con vincristina fue significativamente más alta que las unidades sin tratamiento previo (P>0,05). La inmunofluorescencia para CD44 muestró una alta expresión del marcador de CMC entre mammospheres aisladas. La vincristina en combinación con el cultivo en suspensión puede ser considerado como un método apropiado para aislar CMC.

Expression of CD90 and P75NTR stem cell markers in ameloblastomas: a possible role in their biological behavior

Abstract Multicystic and unicystic ameloblastomas are benign odontogenic tumors that present distinct biological behavior. The investigation of stem cells has become an important branch of tumor biology, with several studies addressing the possible role of these cells in tumor growth, angiogenesis, progression, infiltration and invasiveness. This study evaluated the immunohistochemical expression of CD90(Thy-1) and P75NTR stem cell markers in multicystic and unicystic ameloblastomas. Seventeen (17) samples of ameloblastomas (multicystic, n = 10; unicystic, n = 7) were submitted to immunohistochemical reactions and graded semi-quantitatively. The Kolmogorov-Smirnov test was used to verify possible differences in CD90 and P75NTR expressions between multicystic and unicystic ameloblastomas (p < 0.05). CD90 immunostaining was observed in all multicystic ameloblastoma specimens (n = 10), in the cytoplasm of the fibroblasts and vascular endothelial cells of the tumor stroma, near the neoplastic odontogenic epithelia. The staining of stromal CD90 was significantly higher in multicystic than in unicystic ameloblastomas (p = 0.003). Nuclear P75NTR immunostaining was observed in all ameloblastoma specimens. A significant difference was seen in the epithelial staining of P75NTR between multicystic and unicystic types (p = 0.007). The increased expression of CD90 and P75NTR found in multicystic ameloblastomas suggests a behavioral biological difference between multicystic and unicystic ameloblastomas, as well as a difference in ameloblastoma development.

Characterization of reactive stroma in prostate cancer: involvement of growth factors, metalloproteinase matrix, sexual hormones receptors and prostatic stem cells

ABSTRACT Introduction and Objectives: Reactive Stroma (RStr) is observed in many human cancers and is related to carcinogenesis. The objectives of the present study were to stablish a relationship of the RStr microenvironment with prostate cancer (Pca) through a morphological and molecular characterization, and to identify a possible relationship between RStr with worse prognosis factors and occurrence of malignant prostatic stem cells. Materials and Methods: Forty prostatic samples were selected from men with Pca diagnosis submitted to radical prostatectomy; they were divided in two groups: Group-1 (n=20): samples without reactive stroma; Group-2 (n=20): samples of PCa with intense stroma reaction. Prostatic samples were evaluated for RStr intensity by Masson Trichromic stain and posteriorly submitted to histopathological and immunohistochemistry analysis for antigens: α-actin, vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA, AR, Erα and ERβ. Results: Reactive stroma with intense desmoplastic reactivity was significantly more frequent in intermediate (Gleason 7, 3+4) and high grade tumors (Gleason 7, 4+3). The group with intense stromal reactivity showed significant higher levels of Vimentin, IGF-1, MMP-2, FGF-2, C-Myc, PSCA and ERα. Conclusions: It can be concluded that RStr may be a predictive marker of Pca progression, since it was associated with increase of growth factors, imbalance of androgen and estrogen receptors and presence of malign prostatic stem cells.

A família vivenciando o processo de recuperação da criança pós-alta hospitalar / La familia que vive el proceso de recuperación de niños después del alta hospitalaria / The family living the child recovery process after hospital discharge

RESUMOObjetivo:compreender o significado atribuído pela família à sua vivência no processo de recuperação da criança acometida por doença aguda, após a alta hospitalar e elaborar um modelo teórico a respeito dessa experiência. O Interacionismo Simbólico foi adotado como referencial teórico e a Grounded Theory como metodológico.Método:os dados foram coletados por meio de entrevista e observação participante com 11 famílias, totalizando 15 entrevistas. A análise levou à formulação de um Modelo Teórico composto por dois fenômenos interativos: Mobilizando-se para resgatar o equilíbrio de seu funcionamento e Sofrendo com a possibilidade de reintegrar a criança.Resultados:estes revelaram que a família mantém-se em alerta para identificar precocemente alterações de saúde da criança na tentativa de evitar uma reinternação.Conclusão:os efeitos da doença e hospitalização continuam a manifestar-se no funcionamento familiar, gerando sofrimento mesmo após a alta e a recuperação da criança.

RESUMENObjetivo:comprender el significado atribuido por la familia de su experiencia en la recuperación de los niños afectados por el proceso de la enfermedad aguda, después de la descarga y desarrollar un modelo teórico sobre la experiencia. El Interaccionismo Simbólico fue adoptado como un teórico y la Teoría Fundamentada como metodológico.Método:los datos fueron recolectados a través de entrevistas y observación participante con 11 familias, con un total de 15 entrevistas. El análisis dio lugar a la formulación de un modelo teórico consta de dos fenómenos interactivos: Movilización para restaurar el balance de su funcionamiento y Sufriendo con la posibilidad de reinternar el niño.Resultados:éstos revelaron que la familias e mantiene en alerta para la identificación temprana de la salud el niño en un intento de evitar un reingreso.Conclusión:Los efectos de la enfermedad y la hospitalización aún se manifiesta en el funcionamiento familiar, que produce sufrimiento, incluso después de la descarga y la recuperación del niño.

ABSTRACTObjective:to understand the meaning attributed by the family to its experience in the recovery process of a child affected by an acute disease after discharge, and to develop a theoretical model of this experience. Symbolic interactionism was adopted as a theoretical reference, and grounded theory was adopted as a methodological reference.Method:data were collected through interviews and participant observation with 11 families, totaling 15 interviews. A theoretical model consisting of two interactive phenomena was formulated from the analysis: Mobilizing to restore functional balance and Suffering from the possibility of a child's readmission.Results:the family remains alert to identify early changes in the child's health, in an attempt to avoid rehospitalization.Conclusion:the effects of the disease and hospitalization continue to manifest in family functioning, causing suffering even after the child's discharge and recovery.

Prevalência e fatores associados ao tabagismo entre fumicultores na região Sul do Brasil / Prevalencia y factores asociados al hábito de fumar entre los cultivadores de tabaco en el sur de Brasil / Prevalence and factors associated with smoking among tobacco growers in southern Brazil

RESUMOObjetivo:identificar a prevalência e fatores associados ao tabagismo em fumicultores.Método:estudo descritivo, do tipo transversal. A coleta de dados ocorreu em 2012 por inquérito domiciliar e entrevistas, incluindo aplicação de instrumento estruturado e escala de Fargeström.Resultados:foram incluídos 100 fumicultores, média de idade 46,9±10,8 anos; 90 (90%) casados; 72 (72%) cor branca; composição familiar de 3,7±1,1 pessoas, mediana de filhos de 3(1-3) e média tempo de estudo 6±2,5 anos. Obteve-se prevalência de 17% de fumantes, os quais apresentaram menor escolaridade (p=0,010) e menor número de pessoas no domicílio (p=0,049).Conclusão:a prevalência do tabagismo entre fumicultores foi maior que a média nacional, porém, com baixa dependência da nicotina, o que pode facilitar o processo de cessação do tabagismo. Destaca-se a necessidade de implantar um programa para o controle do tabagismo junto a este grupo.

RESUMENObjetivo:identificar la prevalencia y factores asociados con el consumo de tabaco en el cultivo del tabaco.Método:estudio descriptivo, transversal. Los datos fueron recolectados por medio de entrevistas en el 2012, que incluye la aplicación de un instrumento estructurado y escala Fargeström.Resultados:100 cultivadores se incluyeron, la edad media 46,9±10,8 años; 90(90%) se casó; 72(72%) blanco, la composición familiar de 3,7±1,1 personas, mediana de 3 niños (1-3) y el tiempo promedio de estudio de 6±2,5 años. La prevalencia de tabaquismo fue del 17%, que tenía menos educación (p=0,010) y un menor número de personas en hogar (p=0,049).Conclusión:la prevalencia de tabaquismo entre los productores de tabaco fue mayor que el promedio nacional, pero la dependencia de la nicotina fue baja, lo que puede facilitar el proceso de dejar de fumar. Destaca la necesidad de implementar un programa de control del tabaquismo entre los cultivadores de tabaco.

ABSTRACTObjective:identify the prevalence and factors associated with smoking in tobacco growers.Method:descriptive, cross-sectional research. Data collection occurred in 2012 through household survey and interviews, including application of a structured instrument and scale Fargeström.Results:there were 100 growers included, average age of 46,9 ± 10,8 years; 90(90%) married; 72(72%) white, average family composition 3,7±1,1 people; median number of children 3(1-3), and the average study time 6±2,5. The prevalence of smoking among tobacco growers was 17%, which had less education (p=0.010) and fewer people in the household (p=0.049).Conclusion:the prevalence of smoking among tobacco growers was higher than the national average, but the nicotine dependence was low, which can facilitate the smoking cessation process. Highlights the need to implement a program to control smoking among tobacco growers.

Peritraumatic tonic immobility is associated with PTSD symptom severity in Brazilian police officers: a prospective study

Objective: Peritraumatic reactions feature prominently among the main predictors for development of posttraumatic stress disorder (PTSD). Peritraumatic tonic immobility (PTI), a less investigated but equally important type of peritraumatic response, has been recently attracting the attention of researchers and clinicians for its close association with traumatic reactions and PTSD. Our objective was to investigate the role of PTI, peritraumatic panic, and dissociation as predictors of PTSD symptoms in a cohort of police recruits (n=132). Methods: Participants were asked to complete the following questionnaires during academy training and after the first year of work: Posttraumatic Stress Disorder Checklist - Civilian Version (PCL-C), Physical Reactions Subscale (PRS), Peritraumatic Dissociative Experiences Questionnaire (PDEQ), Tonic Immobility Scale (TIS), and Critical Incident History Questionnaire. Results: Employing a zero-inflated negative binomial regression model, we found that each additional point in the TIS was associated with a 9% increment in PCL-C mean scores (RM = 1.09), whereas for PRS, the increment was 7% (RM = 1.07). As the severity of peritraumatic dissociation increased one point in the PDEQ, the chance of having at least one symptom in the PCL-C increased 22% (OR = 1.22). Conclusions: Our findings highlight the need to expand investigation on the incidence and impact of PTI on the mental health of police officers. .

Cancer Stem Cells in Primary Liver Cancers: Pathological Concepts and Imaging Findings

There is accumulating evidence that cancer stem cells (CSCs) play an integral role in the initiation of hepatocarcinogenesis and the maintaining of tumor growth. Liver CSCs derived from hepatic stem/progenitor cells have the potential to differentiate into either hepatocytes or cholangiocytes. Primary liver cancers originating from CSCs constitute a heterogeneous histopathologic spectrum, including hepatocellular carcinoma, combined hepatocellular-cholangiocarcinoma, and intrahepatic cholangiocarcinoma with various radiologic manifestations. In this article, we reviewed the recent concepts of CSCs in the development of primary liver cancers, focusing on their pathological and radiological findings. Awareness of the pathological concepts and imaging findings of primary liver cancers with features of CSCs is critical for accurate diagnosis, prediction of outcome, and appropriate treatment options for patients.

Cancer stem cells - the current status of an old concept: literature review and clinical approaches

As regards their morphology and biology, tumours consist of heterogeneous cell populations. The cancer stem cell (CSC) hypothesis assumes that a tumour is hierarchically organized and not all of the cells are equally capable of generating descendants, similarly to normal tissue. The only cells being able to self-renew and produce a heterogeneous tumour cell population are cancer stem cells. CSCs probably derive from normal stem cells, although progenitor cells may be taken into consideration as the source of cancer stem cells. CSCs reside in the niche defined as the microenvironment formed by stromal cells, vasculature and extracellular matrix. The CSC assays include FACS sorting, xenotransplantation to immunodeficient mice (SCID), incubation with Hoechst 33342 dye, cell culture in non-adherent conditions, cell culture with bromodeoxyuridine. CSCs have certain properties that make them resistant to anticancer therapy, which suggests they may be the target for potential therapeutic strategies.

Epithelial-mesenchymal transition (EMT): principles and clinical impact in cancer therapy / Transición epitelio-mesenquimática (TEM): principios e impacto clínico en la terapia contra el cáncer

The epithelial-mesenchymal transition (EMT) is a biological phenomenon responsible for the formation of different tissues and organs during normal metazoan development. Because of the connection of the EMT with the pathogenesis of certain diseases, such as cancer, the attention of the scientific community has been directed towards the search for and identification of effective therapeutic targets. These targets include signal transduction in cancerous stem cells and the use of microRNAs, which would inhibit EMT-associated phenotypic changes and tumoral progression. In an attempt to compile relevant and current information, this work addresses concepts that define the EMT and the advances in this field. The wealth of knowledge gained from areas such as the loss of cell polarity and intracellular adhesion complexes, the signaling pathways implicated, microRNA participation in this process, and stemness acquisition in embryonic and cancerous cells, all of which allow for the visualization of promising perspectives, particularly, methods for targeting advanced malignancies, are presented herein.

La transición epitelio-mesenquimática (TEM) es el fenómeno biológico responsable de la formación de los diferentes tejidos y órganos durante el desarrollo normal de los organismos metazoarios. En razón de su conexión con la patogénesis de ciertas enfermedades como el cáncer, la atención de la comunidad científica se ha redireccionado hacia la búsqueda e identificación de blancos terapéuticos efectivos, como la transducción de señales de las células madre cancerosas o la utilización de microARNs, que permitirían bloquear los cambios fenotípicos asociados con la TEM y, por ende, la progresión tumoral. En un intento por recopilar información relevante y actualizada, el presente trabajo aborda conceptos que definen a la TEM y avances alcanzados en este campo. El acervo de conocimiento obtenido en aspectos como pérdida de la polaridad celular y de los complejos de adhesión intercelular, vías de señalización implicadas y participación de los microARNs en el proceso, así como adquisición de stemness o troncalidad, tanto en células embrionarias como cancerosas, hace posible visualizar perspectivas promisorias, en especial en lo que se refiere a las terapias contra las malignidades de alto grado.

Review of stem cell deregulation and breast cancer: An emerging hypothesis.

Cancer is fundamentally a cellular genetic disease capable of transferring the "disease" to the next generation of mutated cells. Similar proliferative and information transferring capacity exists in the stem cells of various organ systems in the human body. Understanding the bio-mechanism of stem cell metabolism and its regulation by signaling molecules and extracellular micro-environment is an important step toward successful prevention and treatment of cancer. According to the cancer stem cell hypothesis, both hereditary and sporadic cancers can arise from deregulation of these cancer stem cells (CSCs), triggered by genetic and environmental factors. It is shown that deregulation of normal self-renewal pathways in undifferentiated breast stem cells or progenitor cells had altered mammary system or progenitor cells, resulting in abnormally differentiated cells in human and rodent breast cancer cell lines. Breakthroughs in molecular pathways have important therapeutic implications. Hence, significant stress is laid on targeting signaling molecules and their micromilieu in breast cancer therapy.

Cultivation and identification of colon cancer stem cell-derived spheres from the Colo205 cell line

Our group established a method to culture spheres under serum-free culture condition. However, the biological characteristics and the tumorigenicity of spheres are unknown. Here, we demonstrate that sphere cells expressed high levels of the putative colorectal cancer stem cell markers CD133 and CD44. The CD133-positive rates were 13.27 ± 5.62, 52.71 ± 16.97 and 16.47 ± 2.45 percent in sphere cells, regular Colo205 cells and differentiated sphere cells, respectively, while the CD44-positive rates were 62.92 ± 8.38, 79.06 ± 12.10 and 47.80 ± 2.5 percent, respectively, and the CD133/CD44-double-positive rates were 10.77 ± 4.96, 46.89 ± 19.17 and 12.41 ± 2.27 percent, respectively (P < 0.05). Cancer sphere cells formed crypt-like structures in 3-D culture. Moreover, cells from cancer spheres exhibited more tumorigenicity than regular Colo205 cells in a xenograft assay. The cancer sphere cells displayed much higher oncogenicity than regular Colo205 cells to initiate neoplasms, as assayed by H&E staining, Musashi-1 staining and electron microscopy. Our findings indicated that the sphere cells were enriched with cancer stem cells (CSCs), and exhibited more proliferation capacity, more differentiation potential and especially more tumorigenicity than regular Colo205 cells in vitro and in vivo. Further isolation and characterization of these CSCs may provide new insights for novel therapeutic targets and prognostic markers.

Molecular signature of cancer stem cells isolated from prostate carcinoma and expression of stem markers in different Gleason grades and metastasis

Prostate cancer (PCa) is the most frequently diagnosed malignancy in men worldwide. Chemotherapy response is very poor and resistance to hormone-based treatments is frequent in advances stages. Recently, tumor-initiating cells or cancer stem cells (CSCs) have been identified in several cancers, including PCa. These cells are thought to be responsible for therapy resistance, relapse and metastasis. In the present work, enriched populations of CSCs were obtained using a mixed procedure that included differential clone-forming ability, sphere growing induction (prostatospheres) and magnetic-associated cell sorting (MACS). Also, stem marker expression was determined in PCa biopsies of different histological grades and metastasis samples. The signature for stem markers of the isolated CSCs was CD133+/CD44+/ABCG2+/ CD24-. Expression of stem markers (CD133, CD44, and ABCG2) was higher in medium Gleason biopsies than in lower and higher grades, and lymph-node and bone metastasis samples. These results suggest that the CSCs in PCa reach an important number in medium Gleason grades, when the tumor is still confined into the gland. At this stage, the surgical treatment is usually with curative intention. However, an important percentage of patients relapse after treatment. Number and signature of CSCs may be a prognosis factor for PCa recurrence.

Sonic Hedgehog in cancer stem cells: a novel link with autophagy

The Sonic Hegdehog/GLI (SHH/GLI) pathway has been extensively studied for its role in developmental and cancer biology. During early embryonic development the SHH pathway is involved mainly in pattern formation, while in latter stages its function in stem cell and progenitor proliferation becomes increasingly relevant. During postnatal development and in adult tissues, SHH/GLI promotes cell homeostasis by actively regulating gene transcription, recapitulating the function observed during normal tissue growth. In this review, we will briefly discuss the fundamental importance of SHH/GLI in tumor growth and cancer evolution and we will then provide insights into a possible novel mechanism of SHH action in cancer through autophagy modulation in cancer stem cells. Autophagy is a homeostatic mechanism that when disrupted can promote and accelerate tumor progression in both cancer cells and the stroma that harbors tumorigenesis. Understanding possible new targets for SHH signaling and its contribution to cancer through modulation of autophagy might provide better strategies in order to design combined treatments and perform clinical trials.