Self-renewal and chemotherapy resistance of p75NTR positive cells in esophageal squamous cell carcinomas

<p>Abstract</p> <p>Background</p> <p>p75^NTRhas been used to isolate esophageal and corneal epithelial stem cells. In the present study, we investigated the expression of p75^NTRin esophageal squamous cell carcinoma (ESCC) and explored the biological properties of p75^NTR+cells.</p> <p>Methods</p> <p>p75^NTRexpression in ESCC was assessed by immunohistochemistry. p75^NTR+and p75^NTR-cells of 4 ESCC cell lines were separated by fluorescence-activated cell sorting. Differentially expressed genes between p75^NTR+and p75^NTR-cells were determined by real-time quantitative reverse transcription-PCR. Sphere formation assay, DDP sensitivity assay, ⁶⁴copper accumulation assay and tumorigenicity analysis were performed to determine the capacity of self-renewal, chemotherapy resistance and tumorigenicity of p75^NTR+cells.</p> <p>Results</p> <p>In ESCC specimens, p75^NTRwas found mainly confined to immature cells and absent in cells undergoing terminal differentiation. The percentage of p75^NTR+cells was 1.6%–3.7% in Eca109 and 3 newly established ESCC cell lines. The expression of Bmi-1, which is associated with self-renewal of stem cells, was significantly higher in p75^NTR+cells. p63, a marker identified in keratinocyte stem cells, was confined mainly to p75^NTR+cells. The expression of CTR1, which is associated with cisplatin (DDP)-resistance, was significantly decreased in p75^NTR+cells. Expression levels of differentiation markers, such as involucrin, cytokeratin 13, β1-integrin and β4-integrin, were lower in p75^NTR+cells. In addition, p75^NTR+cells generated both p75^NTR+and p75^NTR-cells, and formed nonadherent spherical clusters in serum-free medium supplemented with growth factors. Furthermore, p75^NTR+cells were found to be more resistant to DDP and exhibited lower ⁶⁴copper accumulation than p75^NTR-cells.</p> <p>Conclusion</p> <p>Our results demonstrated that p75^NTR+cells possess some characteristics of CSCs, namely, self-renewal and chemotherapy resistance. Chemotherapy resistance of p75^NTR+cells may probably be attributable to decreased expression of CTR1.</p

Dual HER2 blockade in the neoadjuvant and adjuvant treatment of HER2-positive breast cancer

Pooja Advani,1 Lauren Cornell,2 Saranya Chumsri,1 Alvaro Moreno-Aspitia1 1Division of Hematology and Oncology, 2Department of Internal Medicine, Mayo Clinic, Jacksonville, FL, USA Abstract: Human epidermal growth factor receptor 2 (HER2) is a tyrosine kinase transmembrane receptor that is overexpressed on the surface of 15%&ndash;20% of breast tumors and has been associated with poor prognosis. Consistently improved pathologic response and survival rates have been demonstrated with use of trastuzumab in combination with standard chemotherapy in both early and advanced breast cancer. However, resistance to trastuzumab may pose a major problem in the effective treatment of HER2-positive breast cancer. Dual HER2 blockade, using agents that work in a complimentary fashion to trastuzumab, has more recently been explored to evade resistance in both the preoperative (neoadjuvant) and adjuvant settings. Increased effectiveness of dual anti-HER2 agents over single blockade has been recently reported in clinical studies. Pertuzumab in combination with trastuzumab and taxane is currently approved in the metastatic and neoadjuvant treatment of HER2-positive breast cancer. Various biomarkers have also been investigated to identify subsets of patients with HER2-positive tumors who would likely respond best to these targeted therapy combinations. In this article, available trial data regarding efficacy and toxicity of treatment with combination HER2 agents in the neoadjuvant and adjuvant setting have been reviewed, and relevant correlative biomarker data from these trials have been discussed. Keywords: HER2, dual blockade, neoadjuvant, adjuvant, breast cancer, trastuzuma

Beta 2-Adrenergic Receptor in Circulating Cancer-Associated Cells Predicts for Increases in Stromal Macrophages in Circulation and Patient Survival in Metastatic Breast Cancer

The usage of beta blockers in breast cancer (BC) patients is implicated in the reduction in distant metastases, cancer recurrence, and cancer mortality. Studies suggest that the adrenergic pathway is directly involved in sympathetic-driven hematopoietic activation of pro-tumor microenvironmental proliferation and tumor cell trafficking into the circulation. Cancer-associated macrophage-like cells (CAMLs) are pro-tumor polynucleated monocytic cells of hematopoietic origin emanating from tumors which may aid in circulating tumor cell (CTC) dissemination into the circulation. We examined the linkage between Beta-2 adrenergic receptor (B2AR) signaling in CAMLs and CTCs by establishing expression profiles in a model BC cell line (MDA-MB-231). We compared the model to CAMLs and CTCs found in patents. Although internalization events were observed in patients, differences were found in the expression of B2AR between the tumor cell lines and the CAMLs found in patients. High B2AR expression on patients&rsquo; CAMLs was correlated with significantly more CAMLs in the circulation (p = 0.0093), but CTCs had no numerical relationship (p = 0.1565). High B2AR CAML expression was also significantly associated with a larger size of CAMLs (p = 0.0073), as well as being significantly associated with shorter progression-free survival (p = 0.0097) and overall survival (p = 0.0265). These data suggest that B2AR expression on CAMLs is closely related to the activation, intravasation, and growth of CAMLs in the circulation

Physiochemical and antioxidant properties of roselle‐mango juice blends; effects of packaging material, storage temperature and time

A study was conducted to determine the effects of packaging materials, seasonality, storage temperature and time on physiochemical and antioxidant properties of roselle-mango juice blends. Roselle extract (20%, 40%, 60%, and 80%) was mixed with mango juice and stored in glass and plastic bottles at 4°C and 28°C. Total soluble solids, pH, titratable acidity, reducing sugar, color, vitamin C, total monomeric anthocyanins, total phenols, and antioxidant activity (FRAP) were evaluated in freshly prepared juice, and after, 2, 4, and 6 months of storage. The results showed that total soluble solids, reducing sugars, and pH increased with storage times under different storage time, irrespective of packaging materials. The acidity, color, total monomeric anthocyanin, vitamin C, total phenols, and antioxidant activity decreased during storage irrespective of storage temperature and packaging material. Loss of anthocyanins, total phenols, and vitamin C content were higher in blends stored at 28°C than 4°C