SHP2 participates in multiple signaling events by mediating T-cell development and function, and regulates cytokine-dependent granulopoiesis. To explore whether and how SHP2 can regulate bone-marrow eosinophil differentiation, we investigate the contribution of SHP2 in the bone-marrow eosinophil development in allergic mice. Blockade of SHP2 function by SHP2 inhibitor PHPS-1 or conditional shp2 knockdown by adenovirus-inhibited bone-marrow-derived eosinophil differentiation in vitro, with no detectable effects on the apoptosis of eosinophils. Furthermore, SHP2 induced eosinophil differentiation via regulation of the extracellular signal-regulated kinase pathway. Myeloid shp2 conditional knockout mice (LysMcreshp2flox/flox) failed to induce eosinophilia as well as airway hyper-responsiveness. The SHP2 inhibitor PHPS-1 also alleviated eosinophilic airway inflammation and airway hyper-responsiveness, accompanied by significantly reduced levels of systemic eosinophils and eosinophil lineage-committed progenitors in allergic mice. We demonstrate that inhibition of eosinophil development is SHP2-dependent and SHP2 is sufficient to promote eosinophil formation in vivo. Our data reveal SHP2 as a critical regulator of eosinophil differentiation, and inhibition of SHP2 specifically in myeloid cells alleviates allergic airway inflammation.

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We investigated the anti-proliferative effects of recombinant human lysozyme (rHlys) on gastric cancer cell lines and normal human lung fibroblasts. Using conventional molecular cloning techniques we purified rHlys, which we incubated with cultured cells and measured the effects on cell proliferation and viability. At concentrations of 100 and 1000 microg/l, rHlys significantly inhibited the growth of human gastric cancer cell lines. In contrast, 10 and 50 microg/l of rHlys stimulated gastric cancer cell growth. None of the concentrations of rHlys affected cell viability. Only the highest concentration of rHlys (1000 microg/l) inhibited human lung fibroblast growth. Our results suggest that 100 microg/l is the optimum growth inhibiting concentration, which inhibited cancer cell growth but not normal cell growth. Our in vitro findings suggest that genetically engineered rHlys might inhibit human gastric cancer cell proliferation in vivo, so it might warrant further investigation as a potential novel anti-cancer agent.

Background: Amplification or overexpression of HER2 has been shown to play an important role in approximately 30% of breast cancers and is strongly associated with increased recurrence and a worse prognosis. The HER2 extracellular domain (ECD) may be cleaved and shed from the surface of breast cancer cells and serum HER2 ECD levels can be detected by enzyme-linked immunosorbent assay (ELISA). In this study, we explored the relationship between circulating HER2 ECD and tissue HER2 status, then we also examined its predictive value in a cohort of metastatic breast cancer patients. Methods: Two hundred and seven metastatic breast cancer patients from March 2009 to July 2011 were involved in this prospective study at Zhejiang Cancer Hospital. The patients were identified histopathologically as having breast cancer by pathologists and staged mainly based on the pathology, the clinical manifestation, and the imaging findings of CT and MRI according to the classification system of the International Union Against Cancer. Serum HER2 ECD levels were measured by ELISA. Tissue HER2 was determined by IHC and FISH in tumor samples, respectively. Results: The level of serum HER2 ECD was at least more than 15 ng/ml in 31.4% (65/207) metastatic breast cancer patients, 39.1%(43/110) in HER2-positive patients and 23.4%(22/94) in HER2-negative cases, respectively, P = 0.017. We also found that high serum HER2 ECD levels (≥15 ng/ml) were significantly associated with elevated serum CEA (52.1% v 21.5%, OR 3.978, 95%CI 2.138–7.401, P = 0.000), CA125 (48.5% v 23.5%, OR 3.064, 95%CI 1.650–5.691, P = 0.000), CA153 (53.2% v 17.1%, OR 5.48, 95%CI 2.897–10.366, P = 0.000), LDH (53.3% v 23.1%, OR 3.798, 95%CI 2.011–7.173, P = 0.000) and AKP (51.2% v 26.5%, OR 2.911, 95%CI 1.442–5.879, P = 0.002), respectively. For the effect of HER2 ECD on the site of relapse, still there were statistically significant correlation between increased serum HER2 ECD levels and liver involvement (42.7% v 24.0%, OR 2.358, 95%CI 1.294–4.297, P = 0.005), brain metastasis (50.0% v 26.7%, OR 2.744, 95%CI 1.397–5.391, P = 0.003) and visceral involved (37.9% v 14.8%, OR 3.511, 95%CI 1.548–7.961, P = 0.002), respectively. While serum HER2 ECD levels were not related to age, BMI, tumor size, lymph node involvement and hormone receptors status, respectively (P>0.05). Conclusions: Monitoring the circulating levels of the HER2 ECD in patients with metastatic breast cancer provides a real-time assessment of tumor burden and indicates poor prognosis, and may provide important information for reassessment of HER2 in HER2-negative metastatic breast cancer. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P2-05-05.