Search

The tumor microenvironment is a complex mixture of cell types that bi-directionally interact and influence tumor initiation, progression, recurrence, and patient survival. Mesenchymal stromal cells (MSCs) of the tumor microenvironment engage in crosstalk with cancer cells to mediate epigenetic control of gene expression. We identified CD90+ MSCs residing in the tumor microenvironment of patients with invasive breast cancer that exhibit a unique gene expression signature. Single-cell transcriptional analysis of these MSCs in tumor-associated stroma identified a distinct subpopulation characterized by increased expression of genes functionally related to extracellular matrix signaling. Blocking the TGFβ pathway reveals that these cells directly contribute to cancer cell proliferation. Our findings provide novel insight into communication between breast cancer cells and MSCs that are consistent with an epithelial to mesenchymal transition and acquisition of competency for compromised control of proliferation, mobility, motility, and phenotype.

Malignant mesothelioma (MM) is a fatal disease in dire need of therapy. The role of inflammasomes in cancer is not very well studied, however, literature supports both pro-and anti-tumorigenic effects of inflammasomes on cancer depending upon the type of cancer. Asbestos is a causative agent for MM and we have shown before that it causes inflammasome priming and activation in mesothelial cells. MM tumor cells/tissues showed decreased levels of inflammasome components like NLRP3 and caspase-1 as compared to human mesothelial cells or normal tissue counterpart of tumor. Based on our preliminary findings we hypothesized that treatment of MMs with chemotherapeutic drugs may elevate the levels of NLRP3 and caspase-1 resulting in increased cell death by pyroptosis while increasing the levels of IL-1β and other pro-inflammatory molecules. Therefore, a combined strategy of chemotherapeutic drug and IL-1R antagonist may play a beneficial role in MM therapy. To test our hypothesis we used two human MM tumor cell lines (Hmeso, H2373) and two chemotherapeutic drugs (doxorubicin, cisplatin). Through a series of experiments we showed that both chemotherapeutic drugs caused increases in NLRP3 levels, caspase-1 activation, pyroptosis and pro-inflammatory molecules released from MM cells. In vivo studies using SCID mice and Hmeso cells showed that tumors were smaller in combined treatment group of cisplatin and IL-1R antagonist (Anakinra) as compared to cisplatin alone or untreated control groups. Taken together our study suggests that chemotherapeutic drugs in combination with IL-1R antagonist may have a beneficial role in MM treatment.

Asbestos is a group of naturally occurring mineral fibers which are associated in occupational settings with increased risks of malignant mesothelioma (MM), lung cancers, and pulmonary fibrosis (asbestosis). The six recognized types of asbestos fibers (chrysotile, crocidolite, amosite, tremolite, anthophyllite, and actinolite) are different chemically and physically and may have different dose-response relationships in the development of various asbestos-associated diseases. For example, epidemiologic and lung fiber content studies suggest that the pathogenic potential and durability of crocidolite is much greater than chrysotile asbestos in the causation of human MM. We have used isolated mesothelial cells, the target cells of MM, as well as epithelial cells of the lung, the target cells of lung cancers, in vitro to elucidate the dose-response relationships in expression of early response protooncogenes and other genes critical to cell proliferation and malignant transformation in cells exposed to crocidolite and chrysotile asbestos, as well as a number of nonpathogenic fibers and particles. These studies reveal distinct dose-response patterns with different types of asbestos, suggesting a threshold for effects of chrysotile both in in vitro studies and inhalation experiments. The different patterns of gene expression have been confirmed in lungs of rats exposed by inhalation to these types of asbestos. Experiments also suggest no observed adverse effect levels after evaluation of lung injury, inflammation, and fibrosis at lower concentrations of both types of asbestos.

Abstract Objective  To examine the association between breast density and risk of breast ductal carcinoma in situ (DCIS). Methods  We assessed breast density in relation to DCIS risk using combined data from statewide mammography registries in NH and VT. The prospective analyses were based on 572 DCIS cases arising in 154,936 women (58,496 premenopausal and 96,440 postmenopausal). Women in the study were followed on average 4.1 years. Breast density was scored by community radiologists using BIRADS categories (fatty, scattered density, heterogeneous density, extreme density). Results  In premenopausal women, based on 157 cases, the RR for DCIS risk were 0.29 (95% CI: 0.0.04, 2.24) for fatty breasts, 2.06 (95% CI: 1.39, 3.05) for heterogeneous density, and 2.40 (95% CI: 1.47, 3.91) for extreme density, relative to scattered density. In postmenopausal women, based on 369 cases, the RR for DCIS risk were 0.58 (95% CI: 0.37, 0.93) for fatty breasts, 1.41 (95% CI: 1.12, 1.78) for heterogeneous density, and 1.49 (95% CI: 0.93, 2.37) for extreme density, relative to scattered density. The possible interaction between breast density and menopausal status in relation to DCIS risk was not statistically significant. Conclusions  We observed an association between breast density and DCIS risk. Although the association seemed stronger in premenopausal women, there was no evidence of an interaction involving breast density and menopausal status. [ABSTRACT FROM AUTHOR]

Abstract  This is an evaluation of selected process indicators achieved during the first 10 years of performance of the Norwegian Breast Cancer Screening Program (NBCSP). The indicators are compared with the recommended levels given in the European Guidelines. The program invites all female residents aged 50–69 years old to two-view mammography biennially. The attendance rate was 76.2%. The recall rates due to positive mammography were 4.6% and 2.6%, and the detection rates were 6.4 and 4.9 per 1,000 screens, in prevalent and subsequent screens, respectively. Mean tumor size was 14.7 mm for screening detected and 21.2 mm for interval cancers. Axillary lymph node metastases were present in 25.4% and 43.8%, respectively. Detection mode (screening detected or interval cancer) was shown to be an independent predictor for axillary lymph node metastases and high-grade (Grade 3) tumors. The NBCSP meets the recommendations given in the European Guidelines for most of the process indicators evaluated in this study. Based on the results, we anticipate a future mortality reduction from breast cancer in women invited to the NBCSP. [ABSTRACT FROM AUTHOR]