Experimental Generation of Carcinoma-Associated Fibroblasts (CAFs) from Human Mammary Fibroblasts

Carcinomas are complex tissues comprised of neoplastic cells and a non-cancerous compartment referred to as the 'stroma'. The stroma consists of extracellular matrix (ECM) and a variety of mesenchymal cells, including fibroblasts, myofibroblasts, endothelial cells, pericytes and leukocytes(1-3)

Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer

Human CUB and Sushi multiple domains 1 (CSMD1) is a membrane-bound complement inhibitor suggested to act as a putative tumor suppressor gene, since allelic loss of this region encompassing 8p23 including CSMD1 characterizes various malignancies. Here, we assessed the role of CSMD1 as a tumor suppressor gene in the development of breast cancer in vitro and in vivo. We found that human breast tumor tissues expressed CSMD1 at lower levels compared to that in normal mammary tissues. The decreased expression of CSMD1 was linked to a shorter overall survival of breast cancer patients. We also revealed that expression of CSMD1 in human breast cancer cells BT-20 and MDA-MB-231 significantly inhibited their malignant phenotypes, including migration, adhesion and invasion. Conversely, stable silencing of CSMD1 expression in T47D cells enhanced cancer cell migratory, adherent and clonogenic abilities. Moreover, expression of CSMD1 in the highly invasive MDA-MB-231 cells diminished their signaling potential as well as their stem cell-like properties as assessed by measurement of aldehyde dehydrogenase activity. In a xenograft model, expression of CSMD1 blocked the ability of cancer cells to metastasize to secondary sites in vivo, likely via inhibiting local invasion but not the extravasation into distant tissues. Taken together, these findings demonstrate the role of CSMD1 as a tumor suppressor gene in breast cancer

Inhibition of RAC1 activity in cancer associated fibroblasts favours breast tumour development through IL-1β upregulation

Cancer-associated fibroblasts (CAFs) are highly abundant stromal components in the tumour microenvironment. These cells contribute to tumorigenesis and indeed, they have been proposed as a target for anti-cancer therapies. Similarly, targeting the Rho-GTPase RAC1 has also been suggested as a potential therapeutic target in cancer. Here, we show that targeting RAC1 activity, either pharmacologically or by genetic silencing, increases the pro-tumorigenic activity of CAFs by upregulating IL-1β secretion. Moreover, inhibiting RAC1 activity shifts the CAF subtype to a more aggressive phenotype. Thus, as RAC1 suppresses the secretion of IL-1β by CAFs, reducing RAC1 activity in combination with the depletion of this cytokine should be considered as an interesting therapeutic option for breast cancer in which tumour cells retain intact IL-1β signalling.

Correction: Complement inhibitor CSMD1 acts as tumor suppressor in human breast cancer

This article has been corrected: In Figure 4B, the image of MDA-MB-231 cells expressing CSMD1 is an accidental duplicate of the image showing invaded BT-20 cells expressing CSMD1 in Figure 4A. The correct Figure 4, produced using the original data, is shown below. The authors declare that these corrections do not change the results or conclusions of this paper. Original article: Oncotarget. 2016; 7:76920–76933. https://doi.org/10.18632/oncotarget.1272

Diagnosis of osteoporosis from dental panoramic radiographs using the support vector machine method in a computer-aided system

<p>Abstract</p> <p>Background</p> <p>Early diagnosis of osteoporosis can potentially decrease the risk of fractures and improve the quality of life. Detection of thin inferior cortices of the mandible on dental panoramic radiographs could be useful for identifying postmenopausal women with low bone mineral density (BMD) or osteoporosis. The aim of our study was to assess the diagnostic efficacy of using kernel-based support vector machine (SVM) learning regarding the cortical width of the mandible on dental panoramic radiographs to identify postmenopausal women with low BMD.</p> <p>Methods</p> <p>We employed our newly adopted SVM method for continuous measurement of the cortical width of the mandible on dental panoramic radiographs to identify women with low BMD or osteoporosis. The original X-ray image was enhanced, cortical boundaries were determined, distances among the upper and lower boundaries were evaluated and discrimination was performed by a radial basis function. We evaluated the diagnostic efficacy of this newly developed method for identifying women with low BMD (BMD T-score of -1.0 or less) at the lumbar spine and femoral neck in 100 postmenopausal women (≥50 years old) with no previous diagnosis of osteoporosis. Sixty women were used for system training, and 40 were used in testing.</p> <p>Results</p> <p>The sensitivity and specificity using RBF kernel-SVM method for identifying women with low BMD were 90.9% [95% confidence interval (CI), 85.3-96.5] and 83.8% (95% CI, 76.6-91.0), respectively at the lumbar spine and 90.0% (95% CI, 84.1-95.9) and 69.1% (95% CI, 60.1-78.6), respectively at the femoral neck. The sensitivity and specificity for identifying women with low BMD at either the lumbar spine or femoral neck were 90.6% (95% CI, 92.0-100) and 80.9% (95% CI, 71.0-86.9), respectively.</p> <p>Conclusion</p> <p>Our results suggest that the newly developed system with the SVM method would be useful for identifying postmenopausal women with low skeletal BMD.</p

Carcinoma-Associated Fibroblasts Are a Promising Therapeutic Target

Human carcinomas frequently exhibit significant stromal reactions such as the so-called “desmoplastic stroma” or “reactive stroma”, which is characterised by the existence of large numbers of stromal cells and extracellular matrix proteins. Carcinoma-associated fibroblasts (CAFs), which are rich in activated fibroblast populations exemplified by myofibroblasts, are among the predominant cell types present within the tumour-associated stroma. Increased numbers of stromal myofibroblasts are often associated with high-grade malignancies with poor prognoses in humans. CAF myofibroblasts possess abilities to promote primary tumour development, growth and progression by stimulating the processes of neoangiogenesis as well as tumour cell proliferation, survival, migration and invasion. Moreover, it has been demonstrated that CAFs serve as a niche supporting the metastatic colonisation of disseminated carcinoma cells in distant organs. Their contribution to primary and secondary malignancies makes these fibroblasts a potential therapeutic target and they also appear to be relevant to the development of drug resistance and tumour recurrence. This review summarises our current knowledge of tumour-promoting CAFs and discusses the therapeutic feasibility of targeting these cells as well as disrupting heterotypic interactions with other cell types in tumours that may improve the efficacy of current anti-tumour therapies