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An aberrant systemic artery supply results in recurrent infections in the abnormal lung lobe of intralobar pulmonary sequestration (ILS). The mechanisms underlying such persistent inflammation are unknown. Here, we hypothesize that alteration of an endothelial cell niche for alveolar epithelial cells results in the impaired proliferation potential of alveolar progenitor cells, leading to the defective defense mechanism in intralobar pulmonary sequestration. Paraffin sections of lung tissues from patients with intralobar pulmonary sequestration or from healthy controls were collected for analysis of alveolar epithelial alterations in intralobar pulmonary sequestration by quantitative RT-PCR or immunofluorescent staining. Differential transcripts were identified between human pulmonary artery endothelial cells and human aortic endothelial cells by microarray. Validation of microarray data by quantitative PCR analysis indicated that thrombospondin-1 expression level is low in near-lesion part but high in lesion part of ILS lobe as compared to healthy controls. In vitro 3-D matrigel culture was adopted to evaluate the regulation of alveolar progenitor cells by thrombospondin-1 and CD36. We found that the proliferative potential of alveolar type 2 stem/progenitor cells was impaired in intralobar pulmonary sequestration. Mechanistically, we discovered that endothelial thrombospondin-1 promotes alveolar type 2 cell proliferation through the interaction with CD36. These data demonstrate that alveolar stem cells are impaired in the abnormal lobe from patients with intralobar pulmonary sequestration and imply that restoring epithelial integrity can be beneficial for the future treatments of recurrent infections in lung pathologies., Competing Interests: CONFLICTS OF INTEREST The authors indicate no potential conflicts of interest.

Reciprocal interactions between cancers and the surrounding microenvironment have an important role in tumour evolution. In this study, our data suggested that through thrombospondin 1 (TSP1), tumour-associated microvessel provides a dormant niche to sustain inactive status of breast invasive ductal carcinoma (IDC) cells. TSP1 levels in the tumour stroma were negatively correlated with vascular indoleamine 2,3-dioxygenase 1 (IDO1) in IDC tissues. IDO1 is an intracellular enzyme initiating the first and rate-limited step of tryptophan breakdown. Lower stromal TSP1 levels and positive tumour vascular IDO1 staining seems to associate with poor survive of patients with IDC. IDC cells induced a significantly increase in IDO1 expression in endothelial cells (ECs). IFNγ exerts a similar effect on ECs. We hypothesized a tryptophan starvation theory that since tryptophan is essential for the synthesis of TSP1, IDO1 induce a decrease in tryptophan availability and a reduction in TSP1 synthesis in ECs, leading to overcoming the dormancy state of IDC cells and exacerbating conditions such as tumour invasion and metastasis. These findings identify a non-canonical role of IFNγ/IDO1/TSP1 axis in microvascular niche-dominated dormancy of breast invasive ductal carcinoma with a solid foundation for further investigation of therapeutic and prognostic relevance., Competing Interests: CONFLICTS OF INTEREST The authors declare no potential conflicts of interest.

CD47 is a transmembrane protein that functions as a receptor for thrombospondin-1 (TSP1) and a ligand for inhibitory receptor signal-regulatory protein-α (SIRPα). Blocking the interaction between CD47 on tumor cells and SIRPα on macrophages has been shown to induce antitumor responses. Here we investigated the role of CD47 expression in tumor stroma in tumorigenesis by comparing tumor growth in wild-type (WT) and CD47-deficient mice after subcutaneous injection of syngeneic prostate cancer cells. We found that CD47 deficiency in tumor stromal endothelial cells enhances angiogenesis, leading to suppressed tumor necrosis formation and accelerated tumor progression. Tumors from CD47-deficient mice also showed improved vascular integrity and stability, as well as increased expression of vascular endothelial growth factor (VEGF)-A and VEGF receptor 2 (VEGFR2) compared to those from WT mice. Moreover, reduced macrophage recruitment, likely due to decreased TSP1 production, was detected in tumors from CD47-deficient mice. Our results indicate that although treatment with antibody against CD47 induces antitumor immune responses by blocking the inhibitory CD47-SIRPα signaling, this treatment may also potentially promote tumor progression by blocking CD47 signaling in tumor stromal endothelial cells.

Esophageal squamous cell carcinoma (ESCC) is one of the most common malignant neoplasms worldwide. Patients are often diagnosed at advanced stages with poor prognosis due to the absence of obvious early symptoms. Here, we applied a high-throughput serum peptidome analysis to identify circulating peptide markers of ESCC. Weak cationic exchange magnetic beads coupled to matrix-assisted laser desorption/ionization time-of-flight mass spectrometry was used for two-stage proteotypic peptide profiling in complex serum samples collected from 477 cancer patients and healthy controls. We established a genetic algorithm model containing three significantly differentially expressed peptides at 1,925.5, 2,950.6 and 5,900.0 Da with a sensitivity and specificity of 97.00% and 95.92% in the training set and 97.03% and 100.00% in the validation set, respectively. The model's diagnostic capability was significantly better than SCC-Ag and Cyfra 21-1, especially for early stage ESCC, with an achieved sensitivity of 96.94%. Subsequently, these peptides were identified as fragments of AHSG, TSP1 and FGA by linear ion trap-orbitrap hybrid tandem mass spectrometry. Notably, increased tissue and serum levels of TSP1 in ESCC were verified and correlated with disease progression. In addition, tissue TSP1 was an independent poor prognostic factor in ESCC. In conclusion, the newly established circulating peptide panel and identified proteins could serve as potential biomarkers for the early detection and diagnosis of ESCC. Nevertheless, a larger cohort will be required for further unequivocal validation of their clinical application., Competing Interests: The authors have declared that no competing interests exist.