Increased Cycling Cell Numbers and Stem Cell Associated Proteins as Potential Biomarkers for High Grade Human Papillomavirus+ve Pre-Neoplastic Cervical Disease

High risk (oncogenic) human papillomavirus (HPV) infection causes cervical cancer. Infections are common but most clear naturally. Persistent infection can progress to cancer. Pre-neoplastic disease (cervical intraepithelial neoplasia/CIN) is classified by histology (CIN1-3) according to severity. Cervical abnormalities are screened for by cytology and/or detection of high risk HPV but both methods are imperfect for prediction of which women need treatment. There is a need to understand the host virus interactions that lead to different disease outcomes and to develop biomarker tests for accurate triage of infected women. As cancer is increasingly presumed to develop from proliferative, tumour initiating, cancer stem cells (CSCs), and as other oncogenic viruses induce stem cell associated gene expression, we evaluated whether presence of mRNA (detected by qRT-PCR) or proteins (detected by flow cytometry and antibody based proteomic microarray) from stem cell associated genes and/or increased cell proliferation (detected by flow cytometry) could be detected in well-characterised, routinely collected cervical samples from high risk HPV+ve women. Both cytology and histology results were available for most samples with moderate to high grade abnormality. We found that stem cell associated proteins including human chorionic gonadotropin, the oncogene TP63 and the transcription factor SOX2 were upregulated in samples from women with CIN3 and that the stem cell related, cell surface, protein podocalyxin was detectable on cells in samples from a subset of women with CIN3. SOX2, TP63 and human gonadotrophin mRNAs were upregulated in high grade disease. Immunohistochemistry showed that SOX2 and TP63 proteins clearly delineated tumour cells in invasive squamous cervical cancer. Samples from women with CIN3 showed increased proliferating cells. We believe that these markers may be of use to develop triage tests for women with high grade cervical abnormality to distinguish those who may progress to cancer from those who may be treated more conservatively

Characterization of the expression of the pro-metastatic MenaINV isoform during breast tumor progression

Several functionally distinct isoforms of the actin regulatory Mena are produced by alternative splicing during tumor progression. Forced expression of the Mena[superscript INV] isoform drives invasion, intravasation and metastasis. However, the abundance and distribution of endogenously expressed Mena[superscript INV] within primary tumors during progression remain unknown, as most studies to date have only assessed relative mRNA levels from dissociated tumor samples. We have developed a Mena[superscript INV] isoform-specific monoclonal antibody and used it to examine Mena[superscript INV]expression patterns in mouse mammary and human breast tumors. Mena[superscript INV] expression increases during tumor progression and to examine the relationship between Mena[superscript INV] expression and markers for epithelial or mesenchymal status, stemness, stromal cell types and hypoxic regions. Further, while Mena[superscript INV] robustly expressed in vascularized areas of the tumor, it is not confined to cells adjacent to blood vessels. Altogether, these data demonstrate the specificity and utility of the anti-Mena[superscript INV]-isoform specific antibody, and provide the first description of endogenous Mena[superscript INV]protein expression in mouse and human tumors.United States. Dept. of Defense. Breast Cancer Research Program (Grants W81XWH-10-1-0040 and W81XWH-13-1-0031)National Institutes of Health (U.S.) (Grants U54-CA112967 and GM58801)Massachusetts Institute of Technology. Ludwig Center for Molecular Oncolog

Impact of the Microenvironment on Tumour Budding in Colorectal Cancer.

Tumour Budding (TB) is recognized as an adverse prognostic factor in colorectal cancer (CRC). TB is the detachment of isolated cancer cells or small clusters of such cells mainly at the invasion front. One question that arises is of the role of the tumour stroma regarding the permissiveness of the formation and progression of TB. In this review, we will examine potential factors affecting TB, in particular we will analyse the potential effect of inflammation, hypoxia, extracellular matrix and Cancer-Associated Fibroblasts (CAFs).info:eu-repo/semantics/publishe