The Role of Hepatocyte Growth Factor in Obesity-induced Basal-like Breast Cancer

Obesity is a well-known modifiable risk factor for many diseases, including cancer. Recent studies in mice and humans have demonstrated the significance of the microenvironment in shaping cancer risk and progression. This study investigated the obesity-induced hepatocyte growth factor (HGF)/cMET signaling pathway in promoting basal-like breast cancer (BBC), an aggressive triple negative subtype of breast cancer with no targeted therapy. HGF is a secreted protein released from stromal cells in an inactive form. Once activated, HGF binds to its receptor cMET, a proto-oncogene, which activates pro-tumor signaling pathways. We have previously demonstrated that obesity increases HGF/cMET in murine mammary glands and drives early tumor onset in a genetically engineered mouse model (GEMM) of human BBC, C3(1)-Tag mice. To test our hypothesis that weight loss would reverse the effects of obesity, mice were weaned at 3 weeks of age onto either a low fat (10% kcal from fat) or high fat (60% kcal from fat) diet. We sought to investigate changes in the pro-tumor pathway after a diet switch at 10 weeks of age, from 60% kcal from fat to 10%, by inducing weight loss prior to tumor onset. Importantly, HGF/cMET expression in normal mammary glands, and cMET in tumors, was elevated with obesity and was significantly reversed with weight loss. This study also quantified adipocyte area in normal mammary and tumor tissue between the 10% kcal from fat and 60% kcal from fat diets to study diet effects on adipocyte size. Interestingly, many of the HGF/cMET regulators, e.g., activators such as HGF-Activator, and inhibitors such as HGF-Activator Inhibitor were modified in the weight-loss mice between Normal Associated Fibroblasts and Cancer Associated Fibroblasts. Finally, we confirmed that C3(1)-Tag mammary tumor epithelial cells grown in conditioned media from fibroblasts of differing diets, 10% and 60% kcal from fat, have distinctive proliferation indices. In summary, these results indicate that low and high fat diets have differential effects on murine phenotypes, including body weight, body composition, and stromal microenvironment. Importantly, weight loss in adulthood is possible, which reversed the obesity-mediated pro-tumorigenic pathway. Future research aims include implementing weight loss as a preventative measure in human subjects and inhibiting the HGF/cMET pathway to evaluate potential treatment for obesity-driven BBC.Bachelor of Science in Public Healt

Artifacts in Spectral-Domain Optical Coherence Tomography Measurements in Glaucoma

IMPORTANCE Spectral-domain optical coherence tomography (SD-OCT) has an integral role in the diagnosis and treatment of glaucoma. Understanding the types of artifacts commonly seen in the imaging of patients being evaluated for glaucoma will help physicians better implement these data in the care of patients. OBJECTIVES To determine the frequency and distribution of SD-OCT imaging artifacts in patients being evaluated for glaucoma and to provide examples of common artifacts. DESIGN, SETTING, AND PARTICIPANTS A retrospective cross-sectional study design was used to examine SD-OCT images (using Spectralis SD-OCT) of 277 consecutive patients who had a diagnosis of glaucoma of any stage or had suspected glaucoma. Retinal nerve fiber layer (RNFL) and macular thickness scans were included. For each scan, the final printout and the source images that generated the final printout were examined. If present, artifacts were classified as evident on the final printout or not and were categorized as to the primary source of the artifact (eg, ocular pathologic features or technician errors). Examples of common artifacts are provided. MAIN OUTCOMES AND MEASURES The presence of imaging artifacts. RESULTS In 277 consecutive patients, 131 macular thickness scans were obtained, and 277 RNFL scans were obtained. Of the macular thickness scans, 37 (28.2%; 95% CI, 20.8%-36.1%) had imaging artifacts. Six of these artifacts were not obvious on the final printout. Of the RNFL scans, 55 (19.9%; 95% CI, 15.2%-24.6%) contained artifacts. Seven of these artifacts were not evident on the final printout. The most common cause of artifacts for macular thickness and RNFL scans was ocular pathologic features, primarily the presence of an epiretinal membrane. CONCLUSIONS AND RELEVANCE It is likely that SD-OCT-related imaging artifacts occur in 15.2% to 36.1% of scans obtained in patients being evaluated for glaucoma. Some of these artifacts may not be evident on the final printout. Physicians should be alert to the possibility of artifacts, particularly in patients with ocular pathologic features such as an epiretinal membrane

Weight loss reduces basal-like breast cancer through kinome reprogramming

Additional file 1. Tumor burden and growth were not affected by diet. a. Tumor burden was quantified at sacrifice. b. Tumor volume was measured by calipers at detection and sacrifice. (N = 28 10 %; N = 31 60 %; N = 29, 60–10 %)

cMET inhibitor crizotinib impairs angiogenesis and reduces tumor burden in the C3(1)-Tag model of basal-like breast cancer

Epidemiologic studies have associated obesity with increased risk of the aggressive basal-like breast cancer (BBC) subtype. Hepatocyte growth factor (HGF) signaling through its receptor, cMET, is elevated in obesity and is a pro-tumorigenic pathway strongly associated with BBC. We previously reported that high fat diet (HFD) elevated HGF, cMET, and phospho-cMET in normal mammary gland, with accelerated tumor development, compared to low fat diet (LFD)-fed lean controls in a murine model of BBC. We also showed that weight loss resulted in a significant reversal of HFD-induced effects on latency and elevation of HGF/cMET signaling in normal mammary and cMET in normal mammary and tumors. Here, we sought to inhibit BBC tumor progression in LFD- and HFD-fed C3(1)-Tag BBC mice using a small molecule cMET inhibitor, and began crizotinib treatment (50mg/kg body weight by oral gavage) upon identification of the first palpable tumor. We next investigated if administering crizotinib in a window prior to tumor development would inhibit or delay BBC tumorigenesis. Treatment: Crizotinib significantly reduced mean tumor burden by 27.96 and 37.29%, and mean tumor vascularity by 35.04 and 33.52%, in our LFD- and HFD-fed C3(1)-Tag BBC mice, respectively. Prevention: Crizotinib significantly accelerated primary tumor progression in both diet groups but had no effect on total tumor progression or total tumor burden. In sum, cMET inhibition by crizotinib limited tumor development and microvascular density in basal-like tumor-bearing mice but did not appear to be an effective preventive agent for BBC.Electronic supplementary materialThe online version of this article (doi:10.1186/s40064-016-1920-3) contains supplementary material, which is available to authorized users

MOESM3 of Weight loss reduces basal-like breast cancer through kinome reprogramming

Additional file 3. Kinome profiling revealed significant regulation of pathways by HFD that were reversed with weight loss. A and b. Quantitative comparison of kinases in unaffected mammary tissues from mice using MIB/MS was conducted. Legend indicates three iTRAQ runs with 2–4 samples pooled per group per run. The graphs indicates quantitative changes in kinase activity as a ratio of mice fed 60 % (a) or 60–10 % (b) diet relative to mice fed 10 % diet group. Ratio <1 denotes decreased kinase activity and >1 increased kinase activity. Kinase families are indicated (AGC: Containing PKA, PKG, PKC families; CAMK: Calcium/calmodulin-dependent protein kinase; CK1: Casein kinase 1; CMGC: Containing CDK, MAPK, GSK3, CLK families; STE: Homologs of yeast Sterile 7, Sterile 11, Sterile 20 kinases; TK: Tyrosine kinase; TKL: Tyrosine kinase-like). c. Mean kinase activity is reported for mice fed 60 % diet (dark grey) or 60–10 % diet (light grey) compared to mice on 10 % diet group. Error bars are not indicated for clarity. Statistically significant comparisons are reported in Fig. 5d