Obesity-Induced Mast Cell Infiltration and Activation in Normal Mammary Tissue and Claudin-Low Breast Tumors

Obesity is among the most prevalent conditions worldwide: in the United States alone, more than 60% of the population is either overweight or obese. The condition remains a well-known modifiable risk factor for multiple diseases, including cancer. Obesity is characterized by a low-grade smoldering inflammatory state, which both induces and is sustained by many polarized, pro-inflammatory immune cells. Recent studies have also highlighted the role of the immune system in the genesis and progression of cancer, with many immune cell lineages working to promote angiogenesis, tumor growth and metastasis. One of these immune cells lineages are mast cells (MCs), a type of long-lived myeloid stem cell-derived granulocyte that are traditionally known for their role in the allergic response known as anaphylaxis, but also mediate wound healing and vessel formation. MCs play a crucial role in the tumor microenvironment, by secreting proteases, cytokines and other factors that promote angiogenesis, extracellular matrix degradation and metastasis. Previous studies have reported increased mast cell presence in visceral adipose tissue in obesity. Thus, this study investigated whether obesity promotes mast cell infiltration into and activation within normal mammary tissue and claudin-low breast tumors, an aggressive triple negative subtype of breast cancer. To test our hypotheses, we utilized C57BL/6J and FVB/NJ mouse strains. Female C57BL/6J mice were weaned onto either low fat (LFD, 10% kcal from fat) or high fat (HFD, 60% kcal from fat) diet at 3 weeks of age. At 13 weeks of age, C57BL/6J mice underwent syngeneic orthotopic transplant of M-Wnt claudin-low breast cancer cells into their mammary fat pad. In addition, female FVB/NJ mice were randomized to either LFD or HFD at 8 weeks of age; at 13 weeks of age, mice in a Diet Switch (DS) group were also transitioned from HFD to LFD to induce weight loss prior to tumor injection. FVB/NJ mice underwent syngeneic orthotopic transplant of C3-Tag-luc claudin-low breast cancer cells into their mammary fat pad at 18 weeks of age. We sought to measure mast cell infiltration and activation through histological quantification of mast cell density (cells/mm2), and through quantification of Tryptase β-2 mRNA expression levels, respectively. Relative to tumors, higher mast cell density, as well as higher Tryptase β-2 mRNA expression, was observed in normal mammary of C57BL/6J mice. Importantly, in C57BL/6J mice, higher mRNA expression was also observed across tissues in HFD-fed as compared to LFD-fed mice by two-way ANOVA. In FVB/NJ mice, higher MC density was observed in tumors as compared to normal mammary. Furthermore, higher Tryptase expression was observed in normal mammary tissue upon conditions of obesity, and was significantly reversed with weight loss before tumor development. In summary, these results indicate that low and high fat diets have differential effects on murine models, including body weight and body composition, and that high fat diet may influence mast cell activation in normal mammary tissue, independently of mast cell density. This pilot study offers insights into a potential role of obesity in modulating activation of mast cells, emphasizing the need for future investigation into mast cells as mediators of the relationship between obesity and breast cancer risk or progression.Bachelor of Science in Public Healt

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

Trends in oncological imaging during the COVID‐19 pandemic through the vaccination era

Abstract Background This study examines the impact that the COVID‐19 pandemic has had on computed tomography (CT)‐based oncologic imaging utilization. Methods We retrospectively analyzed cancer‐related CT scans during four time periods: pre‐COVID (1/5/20–3/14/20), COVID peak (3/15/20–5/2/20), post‐COVID peak (5/3/20–12/19/20), and vaccination period (12/20/20–10/30/21). We analyzed CTs by imaging indication, setting, and hospital type. Using percentage decrease computation and Student's t‐test, we calculated the change in mean number of weekly cancer‐related CTs for all periods compared to the baseline pre‐COVID period. This study was performed at a single academic medical center and three affiliated hospitals. Results During the COVID peak, mean CTs decreased (−43.0%, p < 0.001), with CTs for (1) cancer screening, (2) initial workup, (3) cancer follow‐up, and (4) scheduled surveillance of previously treated cancer dropping by 81.8%, 56.3%, 31.7%, and 45.8%, respectively (p < 0.001). During the post‐COVID peak period, cancer screenings and initial workup CTs did not return to prepandemic imaging volumes (−11.4%, p = 0.028; −20.9%, p = 0.024). The ED saw increases in weekly CTs compared to prepandemic levels (+31.9%, p = 0.008), driven by increases in cancer follow‐up CTs (+56.3%, p < 0.001). In the vaccination period, cancer screening CTs did not recover to baseline (−13.5%, p = 0.002) and initial cancer workup CTs doubled (+100.0%, p < 0.001). The ED experienced increased cancer‐related CTs (+75.9%, p < 0.001), driven by cancer follow‐up CTs (+143.2%, p < 0.001) and initial workups (+46.9%, p = 0.007). Conclusions and relevance The pandemic continues to impact cancer care. We observed significant declines in cancer screening CTs through the end of 2021. Concurrently, we observed a 2× increase in initial cancer workup CTs and a 2.4× increase in cancer follow‐up CTs in the ED during the vaccination period, suggesting a boom of new cancers and more cancer examinations associated with emergency level acute care