The precise role of fibrocytes in angiogenesis in wounds remains unclear. We therefore demonstrated the specific changes in fibrocyte accumulation for angiogesis in basic fibroblast growth factor ...(bFGF)–treated wounds. bFGF-treated wounds exhibited marked formation of arterioles and inhibition of podoplanin+ lymph vessels that were lacking in vascular endothelial growth factor-A–treated wounds. Real-time PCR in bFGF-treated wounds manifested enhanced expression of CD34, CD31, and bFGF mRNA and reduced expression of podoplanin and collagen type I, III, and IV mRNA. Double immunofluorescence staining focusing on fibrocyte detection in bFGF-treated wounds showed markedly increased formation of capillary-like structures composed of CD34+ /procollagen I+ fibrocytes, with a lack of capillary-like structures formed by CD45+ /procollagen I+ or CD11b+ /procollagen I+ fibrocytes. However, vascular endothelial growth factor-A–treated wounds lacked capillary-like structures composed of CD34+ /procollagen I+ fibrocytes, with increased numbers of CD34+ /fetal liver kinase-1+ endothelial progenitor cells. Furthermore, fibroblast growth factor receptor 1 siRNA injection into wounds, followed by bFGF, markedly inhibited the formation of capillary-like structures composed of CD34+ /procollagen I+ fibrocytes, together with inhibited mRNA expression of CD34 and CD31 and enhanced mRNA expression of collagen type I, indicating the requirements of bFGF/fibroblast growth factor receptor 1 system for capillary structure formation. This study highlighted the angiogenic properties of CD34+ /procollagen I+ fibrocytes specifically induced by bFGF, which provides new insight into the active contribution of fibrocytes for vascular formation during wound healing.
Lung adenocarcinomas presenting as solid nodules are occasionally diagnosed as lepidic predominant lesions. The aim of this study was to clarify the histological structure and to identify factors ...predictive of lepidic predominant lesions. We retrospectively reviewed 38 patients that underwent lobectomy for small (≤ 2 cm) adenocarcinoma presenting as solid nodules. Resected tumor slides were reviewed and histological components were evaluated. Clinical and radiological data were analyzed to identify factors predictive of lepidic predominant lesions. Of 38 solid nodules, 9 (23.7%) nodules were lepidic predominant lesions. Five-year disease-free survival (DFS) rates were 100% for lepidic predominant lesions (n = 9) and 74.6% for non-lepidic predominant lesions (n = 29). Mean CT values (p = 0.039) and maximum CT values (p = 0.015) were significantly lower in lepidic predominant lesions compared with non-lepidic predominant lesions. For the prediction of lepidic predominant lesions, the sensitivity and specificity of mean CT value (cutoff, - 150 HU) were 77.8% and 82.8%, respectively, and those of maximum CT value (cutoff, 320 HU) were 77.8% and 72.4%, respectively. A combination of mean and maximum CT values (cutoffs of - 150 HU and 380 HU for mean CT value and maximum CT value, respectively) more accurately predicted lepidic predominant lesions, with a sensitivity and specificity of 77.8% and 86.2%, respectively. The prognosis of lepidic predominant lesions was excellent, even for solid nodules. The combined use of mean and maximum CT values was useful for predicting lepidic predominant lesions, and may help predict prognosis.
Triple-negative breast cancer (TNBC) lacks an effective treatment target and is usually associated with a poor clinical outcome; however, hormone unresponsiveness, which is the most important ...biological characteristic of TNBC, only means the lack of nuclear estrogenic signaling through the classical estrogen receptor (ER), ER-α. Several sex steroid receptors other than ER-α: androgen receptor (AR), second ER, ER-β, and non-nuclear receptors represented by G-protein-coupled estrogen receptor (GPER), are frequently expressed in TNBC and their biological and clinical importance has been suggested by a large number of studies. Despite the structural similarity between each sex steroid hormone (androgens and estrogens) or each receptor (AR and ER-β), and similarity in the signaling mechanisms of these hormones, most studies or reviews focused on one of these receptors, and rarely reviewed them in a comprehensive way. Considering the coexistence of these hormones and their receptors in TNBC in a clinical setting, a comprehensive viewpoint would be important to correctly understand the association between the carcinogenic mechanism or pathobiology of TNBC and sex steroid hormones. In this review, the carcinogenic or pathobiological role of sex steroid hormones in TNBC is considered, focusing on the common and divergent features of the action of these hormones.
Interleukin (IL)-11 is a member of the IL-6 family of cytokines and is involved in multiple cellular responses, including tumor development. However, the origin and functions of IL-11-producing ...(IL-11
) cells are not fully understood. To characterize IL-11
cells in vivo, we generate Il11 reporter mice. IL-11
cells appear in the colon in murine tumor and acute colitis models. Il11ra1 or Il11 deletion attenuates the development of colitis-associated colorectal cancer. IL-11
cells express fibroblast markers and genes associated with cell proliferation and tissue repair. IL-11 induces the activation of colonic fibroblasts and epithelial cells through phosphorylation of STAT3. Human cancer database analysis reveals that the expression of genes enriched in IL-11
fibroblasts is elevated in human colorectal cancer and correlated with reduced recurrence-free survival. IL-11
fibroblasts activate both tumor cells and fibroblasts via secretion of IL-11, thereby constituting a feed-forward loop between tumor cells and fibroblasts in the tumor microenvironment.
Fibrosing interstitial lung disease (ILD) develops due to the impaired reparative processes following lung tissue damage. Cellular senescence has been reported to contribute to the progression of ...fibrosis. However, the mechanisms by which these senescent cells initiate and/or drive the progression of lung tissue fibrosis are not yet fully understood. We demonstrated that p21
- and p16
-pathway-dependent senescence in type 2 alveolar epithelial cells (AEC2) were both involved in the initiation and progression of lung fibrosis in murine bleomycin (BLM)-induced ILD. p21
-senescent AEC2 emerged rapidly, as early as 1 day after the intratracheal instillation of BLM. Their number subsequently increased and persisted until the later fibrosis phase. Very few p16
-senescent AEC2 emerged upon the instillation of BLM, and their increase was slower and milder than that of p21
AEC2. AEC2 enriched with senescent cells sorted from BLM-ILD lungs expressed senescence-associated secretory phenotype (SASP)-related genes, including
,
,
,
,
, and
, at the initiation and chronic phases of fibrosis, exhibiting distinct expression patterns of magnitude that were dependent on the disease phase. Ly6C
inflammatory monocytes increased in the lungs immediately after the instillation of BLM and interstitial macrophages increased from day 3. The expression of
and
was upregulated as early as day 1, indicating the activation of fibroblasts. We speculated that IL-6, plasminogen activator inhibitor-1 (PAI-1), and TGF-β contributed to the accumulation of senescent cells during the progression of fibrosis in an autocrine and paracrine manner. In addition, CCL2, produced in large amounts by senescent AEC2, may have induced the infiltration of Ly6C
inflammatory monocytes in the early phase, and TGF-β and PDGFa from senescent AEC2 may contribute to the activation of fibroblasts in the very early phases. Our study indicated that senescent AEC2 plays a role in the pathogenesis of fibrosing ILD throughout the course of the disease and provides insights into its pathogenesis, which may lead to the development of new therapeutic methods targeting senescent cells or SASP molecules.
OBJECTIVE—The aim of this study was to investigate the influence of a myocardial bridge (MB) on atherosclerosis development in the left anterior descending artery of the normal heart and the ...importance of traditional risk factors (RFs). An additional objective was to determine the correlation between intimal thickening and luminal narrowing.
APPROACH AND RESULTS—The left anterior descending artery from 150 autopsied hearts was treated with formalin perfusion fixation, and each left anterior descending artery was serially cross-sectioned. The intima–media and luminal stenosis ratios were examined using computer-assisted histomorphometry. The luminal stenosis ratio was closely correlated with the intima–media ratio (r=0.792; P<0.001). When an MB was present, the luminal stenosis ratios proximal to the MB in the RF (+) group were significantly greater than those in the RF (−) group (P=0.022 by a multiple comparison test), but there were no differences between the RF (+) and RF (−) groups when an MB was absent. In addition, the site of the greatest stenosis in the MB (+) RF (+) group was 2.5 cm proximal to the MB entrance. Multivariate analyses indicated that age was an independent factor for luminal stenosis ratios ≥50% and 60% (P=0.002 and 0.029, respectively). Furthermore, the presence of an MB plus RFs was an independent factor for a luminal stenosis ratio ≥70% (P=0.037).
CONCLUSIONS—An MB enhances left anterior descending artery atherosclerosis development at a site proximal to the MB entrance, particularly in subjects who have some RFs.
Ulcerative colitis (UC) is characterized by chronic inflammation in the colonic mucosa and submucosa with repeating relapse and remission, but the pathogenesis is unknown. Patients with long‐standing ...UC are at high risk of neoplasm development. The aim of the present study was to identify molecules whose expression is associated with UC and UC‐associated colorectal cancer (UCCA). Biopsy specimens from UC and normal colonic mucosae were analyzed using a proteomics approach, in which carbonic anhydrase 2 (CA2) was identified as a molecule downregulated in UC mucosae. Immunohistochemically, CA2 expression was detected in normal and diverticulitis mucosal epithelia, and its expression decreased as UC activity increased. CA2 expression was almost undetectable in UCCA. We also analyzed the expression of another carbonic anhydrase, CA9, and its upstream molecule, hypoxia‐inducible factor‐1α (HIF‐1α), both of which are induced under hypoxic conditions. It was revealed that CA9 expression was relatively low in normal, diverticulitis and UC mucosae, and was upregulated in UCCA. HIF‐1α expression was consistently low in all tissue types examined. In conclusion, these results suggest that CA2 and CA9 may be possible indicators of UC activity and UCCA development, respectively.
Sjögren's syndrome (SS) is an autoimmune disease in which exocrine tissues are affected by cellular and humoral immunity. As a result, the salivary and lacrimal glands of patients with SS are ...damaged, leading to xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Because experimental approaches to investigate SS pathogenesis in human patients are limited, development of a mouse model is indispensable for understanding the disease. In this study, we show that special AT-rich sequence binding protein-1 conditional knockout (SATB1cKO) mice, in which the SATB1 gene is specifically deleted from hematopoietic cells, develop SS by 4 wk of age, soon after weaning. Female mice presented an earlier onset of the disease than males, suggesting that female SATB1cKO mice are more susceptible to SS. T cell-dominant immune cell infiltration was observed in the salivary glands of 4 wk old SATB1cKO mice, and the frequency of B cells gradually increased as the mice aged. Consistently, levels of anti-SSA and anti-SSB Abs were increased around 8 wk of age, after salivary production reached its lowest level in SATB1cKO mice. These results suggest that SATB1cKO mice can be a novel SS model, in which the progression and characteristics of the disease resemble those of human SS.
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