The transcriptional landscape of cancer stem-like cell functionality in breast cancer.

BACKGROUND: Cancer stem-like cells (CSCs) have been extensively researched as the primary drivers of therapy resistance and tumor relapse in patients with breast cancer. However, due to lack of specific molecular markers, increased phenotypic plasticity and no clear clinicopathological features, the assessment of CSCs presence and functionality in solid tumors is challenging. While several potential markers, such as CD24/CD44, have been proposed, the extent to which they truly represent the stem cell potential of tumors or merely provide static snapshots is still a subject of controversy. Recent studies have highlighted the crucial role of the tumor microenvironment (TME) in influencing the CSC phenotype in breast cancer. The interplay between the tumor and TME induces significant changes in the cancer cell phenotype, leading to the acquisition of CSC characteristics, therapeutic resistance, and metastatic spread. Simultaneously, CSCs actively shape their microenvironment by evading immune surveillance and attracting stromal cells that support tumor progression. METHODS: In this study, we associated in vitro mammosphere formation assays with bulk tumor microarray profiling and deconvolution algorithms to map CSC functionality and the microenvironmental landscape in a large cohort of 125 breast tumors. RESULTS: We found that the TME score was a significant factor associated with CSC functionality. CSC-rich tumors were characterized by an immune-suppressed TME, while tumors devoid of CSC potential exhibited high immune infiltration and activation of pathways involved in the immune response. Gene expression analysis revealed IFNG, CXCR5, CD40LG, TBX21 and IL2RG to be associated with the CSC phenotype and also displayed prognostic value for patients with breast cancer. CONCLUSION: These results suggest that the characterization of CSCs content and functionality in tumors can be used as an attractive strategy to fine-tune treatments and guide clinical decisions to improve patients therapy response.

Follicle-stimulating hormone receptors: A comparison of commercially-available monoclonal and polyclonal antibodies as immunohistochemical markers for cancer research.

PURPOSE: In recent studies, follicle-stimulating hormone receptors (FSHRs) have been reported in a wide range of malignant and benign tumours, depending on the type of antibody used. Using two commercially available antibodies (monoclonal and polyclonal), the current research attempted to demonstrate the usefulness of each antibody for investigating FSHRs in non-canonical tissues. Further, we sought to replicate the results of a major study which demonstrated the presence of FSHRs in the endothelial cells of perineoplastic blood vessels. METHODS: Immunostaining was performed on 16 surgically excised benign and malignant tumor tissue samples using both monoclonal and polyclonal anti-FSHR antibodies. RESULTS: Positive staining of FSHRs was heterogeneous among the tissue samples used for analysis, and was confirmed not only in tumour and endothelial cells of perineoplastic blood vessels, but also in benign and normal cells. Based on our findings, FSHR staining using a polyclonal antibody appeared to be highly sensitive, but with a relatively low specificity. Comparatively, immunoreactivity using a monoclonal antibody appeared to show high specificity, but relatively low sensitivity. Although the selected monoclonal antibody for FSHRs seemed to be more specific than the polyclonal variant, neither exhibited a high overall specificity. Neither of the antibodies assessed in the present research could replicate the results of the aforementioned major study. CONCLUSIONS: In conclusion, neither of the two commercially available antibodies seem to be appropriate for investigating FSHRs in non-canonical tissues and, by extension, their role in carcinogenesis.

Follicle-stimulating hormone receptors: a new immunohistochemical marker in cancers?

PURPOSE: Follicle-stimulating hormone receptors (FSHR) have been reported in ovarian cancer and prostate cancer cells, but recent studies have highlighted their presence in the endothelium of blood vessels belonging to multiple neoplasias. Current research attempts to determine the role of FSHR in neoplastic proliferation and possible therapeutic or diagnostic implications. This paper aimed to analyze articles that have revealed the presence and/or role of FSHR in various neoplasms in humans. METHODS: After performing an extensive search of MEDLINE/ PubMed using MeSH terms "follicle-stimulating hormone receptors" and "cancer", 22 original articles were found relevant for the subject proposed for analysis. RESULTS: FSHR were found in all neoplasms studied, being present in both tumor cells and endothelial cells of intraand perineoplasic blood vessels. Although, the presence of these receptors seemed to be ubiquitary, conclusion and the exact role of these receptors could not be stated due to heterogeneous nature of the existing studies. CONCLUSIONS: Although extensive research studies are needed in order to elucidate the exact role of FSHRs and their utility in clinical practice, joint efforts in studying their implication in neoplastic processes can lead to the use of new diagnostic and therapeutic strategies for cancer patients.

Gene expression profiling reveals activation of the FA/BRCA pathway in advanced squamous cervical cancer with intrinsic resistance and therapy failure.

BACKGROUND: Advanced squamous cervical cancer, one of the most commonly diagnosed cancers in women, still remains a major problem in oncology due to treatment failure and distant metastasis. Antitumor therapy failure is due to both intrinsic and acquired resistance; intrinsic resistance is often decisive for treatment response. In this study, we investigated the specific pathways and molecules responsible for baseline therapy failure in locally advanced squamous cervical cancer. METHODS: Twenty-one patients with locally advanced squamous cell carcinoma were enrolled in this study. Primary biopsies harvested prior to therapy were analyzed for whole human gene expression (Agilent) based on the patient's 6 months clinical response. Ingenuity Pathway Analysis was used to investigate the altered molecular function and canonical pathways between the responding and non-responding patients. The microarray results were validated by qRT-PCR and immunohistochemistry. An additional set of 24 formalin-fixed paraffin-embedded cervical cancer samples was used for independent validation of the proteins of interest. RESULTS: A 2859-gene signature was identified to distinguish between responder and non-responder patients. 'DNA Replication, Recombination and Repair' represented one of the most important mechanisms activated in non-responsive cervical tumors, and the 'Role of BRCA1 in DNA Damage Response' was predicted to be the most significantly altered canonical pathway involved in intrinsic resistance (p = 1.86E-04, ratio = 0.262). Immunohistological staining confirmed increased expression of BRCA1, BRIP1, FANCD2 and RAD51 in non-responsive compared with responsive advanced squamous cervical cancer, both in the initial set of 21 cervical cancer samples and the second set of 24 samples. CONCLUSIONS: Our findings suggest that FA/BRCA pathway plays an important role in treatment failure in advanced cervical cancer. The assessment of FANCD2, RAD51, BRCA1 and BRIP1 nuclear proteins could provide important information about the patients at risk for treatment failure.