Targeting breast cancer stem cells: fishing season open!

Studies describing the tumor as a hierarchically organized cell population have changed the classical oncogenesis view and propose new therapeutic strategies. Cancer stem cells (CSCs) are thought to sustain tumor initiation/maintenance, therapy resistance, and systemic metastases. Targeting this tumor cell population is crucial to achieve a true cancer cure. A large research effort is now aiming to develop drugs targeting CSCs, based either on a priori understanding of key pathways regulating CSC biology or on high-throughput screening to identify novel targets and compounds

Lack of correlation of stem cell markers in breast cancer stem cells

BACKGROUND: Various markers are used to identify the unique sub-population of breast cancer cells with stem cell properties. Whether these markers are expressed in all breast cancers, identify the same population of cells, or equate to therapeutic response is controversial. METHODS: We investigated the expression of multiple cancer stem cell markers in human breast cancer samples and cell lines in vitro and in vivo, comparing across and within samples and relating expression with growth and therapeutic response to doxorubicin, docetaxol and radiotherapy. RESULTS: CD24, CD44, ALDH and SOX2 expression, the ability to form mammospheres and side-population cells are variably present in human cancers and cell lines. Each marker identifies a unique rather than common population of cancer cells. In vivo, cells expressing these markers are not specifically localized to the presumptive stem cell niche at the tumour/stroma interface. Repeated therapy does not consistently enrich cells expressing these markers, although ER-negative cells accumulate. CONCLUSIONS: Commonly employed methods identify different cancer cell sub-populations with no consistent therapeutic implications, rather than a single population of cells. The relationships of breast cancer stem cells to clinical parameters will require identification of specific markers or panels for the individual cancer

Nanomechanical probing of the layer/substrate interface of an exfoliated InSe sheet on sapphire

Van der Waals (vdW) layered crystals and heterostructures have attracted substantial interest for potential applications in a wide range of emerging technologies. An important, but often overlooked, consideration in the development of implementable devices is phonon transport through the structure interfaces. Here we report on the interface properties of exfoliated InSe on a sapphire substrate. We use a picosecond acoustic technique to probe the phonon resonances in the InSe vdW layered crystal. Analysis of the nanomechanics indicates that the InSe is mechanically decoupled from the substrate and thus presents an elastically imperfect interface. A high degree of phonon isolation at the interface points toward applications in thermoelectric devices, or the inclusion of an acoustic transition layer in device design. These findings demonstrate basic properties of layered structures and so illustrate the usefulness of nanomechanical probing in nanolayer/nanolayer or nanolayer/substrate interface tuning in vdW heterostructures

A rare case of a retroperitoneal enterogenous cyst with in-situ adenocarcinoma

<p>Abstract</p> <p>Background</p> <p>Retroperitoneal enterogenous cysts are uncommon and adenocarcinoma within such cysts is a rare complication.</p> <p>Case presentation</p> <p>We present the third described case of a retroperitoneal enterogenous cyst with adenocarcinomatous changes and only the second reported case whereby the cyst was not arising from any anatomical structure.</p> <p>Conclusion</p> <p>This case demonstrates the difficulties in making a diagnosis as well as the importance of a multi-disciplinary approach, and raises further questions regarding post-operative treatment with chemotherapy.</p

Preferential antitumor effect of the Src inhibitor dasatinib associated with a decreased proportion of aldehyde dehydrogenase 1-positive cells in breast cancer cells of the basal B subtype

<p>Abstract</p> <p>Background</p> <p>Recent studies have suggested that the Src inhibitor dasatinib preferentially inhibits the growth of breast cancer cells of the basal-like subtype. To clarify this finding and further investigate combined antitumor effects of dasatinib with cytotoxic agents, a panel of breast cancer cell lines of various subtypes was treated with dasatinib and/or chemotherapeutic agents.</p> <p>Methods</p> <p>Seven human breast cancer cell lines were treated with dasatinib and/or seven chemotherapeutic agents. Effects of the treatments on c-Src activation, cell growth, cell cycle, apoptosis and the proportion of aldehyde dehydrogenase (ALDH) 1-positive cells were examined.</p> <p>Results</p> <p>The 50%-growth inhibitory concentrations (IC₅₀s) of dasatinib were much lower in two basal B cell lines than those in the other cell lines. The IC₅₀s of chemotherapeutic agents were not substantially different among the cell lines. Dasatinib enhanced antitumor activity of etoposide in the basal B cell lines. Dasatinib induced a G1-S blockade with a slight apoptosis, and a combined treatment of dasatinib with etoposide also induced a G1-S blockade in the basal B cell lines. Dasatinib decreased the expression levels of phosphorylated Src in all cell lines. Interestingly, dasatinib significantly decreased the proportion of ALDH1-positive cells in the basal B cell lines but not in the other cell lines.</p> <p>Conclusions</p> <p>The present study indicates that dasatinib preferentially inhibits the growth of breast cancer cells of the basal B subtype associated with a significant loss of putative cancer stem cell population. A combined use of dasatinib with etoposide additively inhibits their growth. Further studies targeting breast cancers of the basal B subtype using dasatinib with cytotoxic agents are warranted.</p

Age determines the prognostic role of the cancer stem cell marker aldehyde dehydrogenase-1 in breast cancer

<p>Abstract</p> <p>Background</p> <p>The purpose of this study was to compare the expression and the prognostic effect of the breast cancer stem cell marker aldehyde dehydrogenase-1 (ALDH1) in young and elderly breast cancer patients.</p> <p>Methods</p> <p>The study population (N = 574) consisted of all early breast cancer patients primarily treated with surgery in our center between 1985 and 1994. Median follow-up was 17.9 years (range: 0.1 to 23.5). Tissue microarray slides were immunohistochemically stained for ALDH1 expression and quantified by two independent observers who were blinded to clinical outcome. Assessment of the prognostic effect of ALDH1 expression was stratified according to age and systemic treatment.</p> <p>Results</p> <p>Complete lack of expression of ALDH1 was found in 40% of tumors. With increasing age more tumors showed complete absence of ALDH1 expression (<it>P </it>< .001). In patients aged > 65 years, ALDH1 status was not associated with any clinical outcome. Conversely, in patients aged < 65 years, ALDH1 positivity was an independent risk factor of worse outcome for relapse free period (hazard ratio = 1.71 (95% CI, 1.09 to 2.68); <it>P </it>= .021) and relative survival (relative excess risks of death = 2.36 (95% CI, 1.22 to 3.68); <it>P </it>= .016). Ten-year relative survival risk was 57% in ALDH1-positive patients compared to 83% in ALDH1-negative patients.</p> <p>Conclusion</p> <p>ALDH1 expression and its prognostic effect are age-dependent. Our results support the hypothesis that breast cancer biology is different in elderly patients compared to their younger counterparts and emphasizes the importance of taking into consideration age-specific interactions in breast cancer research.</p

Expression of the stem cell marker ALDH1 in BRCA1 related breast cancer

Introduction The BRCA1 protein makes mammary stem cells differentiate into mature luminal and myoepithelial cells. If a BRCA1 mutation results in a differentiation block, an enlarged stem cell component might be present in the benign tissue of BRCA1 mutation carriers, and these mammary stem cells could be the origin of BRCA1 related breast cancer. Since ALDH1 is a marker of both mammary stem cells and breast cancer stem cells, we compared ALDH1 expression in malignant tissue of BRCA1 mutation carriers to non-carriers. Methods Forty-one BRCA1 related breast cancers and 41 age-matched sporadic breast cancers were immunohistochemically stained for ALDH1. Expression in epithelium and stroma was scored and compared. Results Epithelial (P=0.001) and peritumoral (P=0.001) ALDH1 expression was significantly higher in invasive BRCA1 related carcinomas compared to sporadic carcinomas. Intratumoral stromal ALDH1 expression was similarly high in both groups. ALDH1 tumor cell expression was an independent predictor of BRCA1 mutation status. Conclusion BRCA1 related breast cancers showed significantly more frequent epithelial ALDH1 expression, indicating that these hereditary tumors have an enlarged cancer stem cell component. Besides, (peritumoral) stromal ALDH1 expression was also more frequent in BRCA1 mutation carriers. ALDH1 may therefore be a diagnostic marker and a therapeutic target of BRCA1 related breast cancer

Cancer stem cell markers in breast cancer: pathological, clinical and prognostic significance

INTRODUCTION: The cancer stem cell (CSC) hypothesis states that tumours consist of a cellular hierarchy with CSCs at the apex driving tumour recurrence and metastasis. Hence, CSCs are potentially of profound clinical importance. We set out to establish the clinical relevance of breast CSC markers by profiling a large cohort of breast tumours in tissue microarrays (TMAs) using immunohistochemistry (IHC). METHODS: We included 4, 125 patients enrolled in the SEARCH population-based study with tumours represented in TMAs and classified into molecular subtype according to a validated IHC-based five-marker scheme. IHC was used to detect CD44/CD24, ALDH1A1, aldehyde dehydrogenase family 1 member A3 (ALDH1A3) and integrin alpha-6 (ITGA6). A 'Total CSC' score representing expression of all four CSC markers was also investigated. Association with breast cancer specific survival (BCSS) at 10 years was assessed using a Cox proportional-hazards model. This study was complied with REMARK criteria. RESULTS: In ER negative cases, multivariate analysis showed that ITGA6 was an independent prognostic factor with a time-dependent effect restricted to the first two years of follow-up (hazard ratio (HR) for 0 to 2 years follow-up, 2.4; 95% confidence interval (95% CI), 1.2 to 4.8; P = 0.009). The composite 'Total CSC' score carried independent prognostic significance in ER negative cases for the first four years of follow-up (HR for 0 to 4 years follow-up, 1.3; 95% CI, 1.1 to 1.6; P = 0.006). CONCLUSIONS: Breast CSC markers do not identify identical subpopulations in primary tumours. Both ITGA6 and a composite Total CSC score show independent prognostic significance in ER negative disease. The use of multiple markers to identify tumours enriched for CSCs has the greatest prognostic value. In the absence of more specific markers, we propose that the effective translation of the CSC hypothesis into patient benefit will necessitate the use of a panel of markers to robustly identify tumours enriched for CSCs

A novel spontaneous model of epithelial-mesenchymal transition (EMT) using a primary prostate cancer derived cell line demonstrating distinct stem-like characteristics

Cells acquire the invasive and migratory properties necessary for the invasion-metastasis cascade and the establishment of aggressive, metastatic disease by reactivating a latent embryonic programme: epithelial-to-mesenchymal transition (EMT). Herein, we report the development of a new, spontaneous model of EMT which involves four phenotypically distinct clones derived from a primary tumour-derived human prostate cancer cell line (OPCT-1), and its use to explore relationships between EMT and the generation of cancer stem cells (CSCs) in prostate cancer. Expression of epithelial (E-cadherin) and mesenchymal markers (vimentin, fibronectin) revealed that two of the four clones were incapable of spontaneously activating EMT, whereas the others contained large populations of EMT-derived, vimentin-positive cells having spindle-like morphology. One of the two EMT-positive clones exhibited aggressive and stem cell-like characteristics, whereas the other was non-aggressive and showed no stem cell phenotype. One of the two EMT-negative clones exhibited aggressive stem cell-like properties, whereas the other was the least aggressive of all clones. These findings demonstrate the existence of distinct, aggressive CSC-like populations in prostate cancer, but, importantly, that not all cells having a potential for EMT exhibit stem cell-like properties. This unique model can be used to further interrogate the biology of EMT in prostate cancer