Yuuji Aoki, Yuki Fukumura, Jun Nakahodo, Yoshihiro Mezawa, Yifare Maimaitiaili, Mulading Maimaitituerxun, Takashi Yao
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引用次数: 0
Abstract
Introduction: Identifying pathological markers to differentiate between high- and low-grade pancreatic intraepithelial neoplasia (PanIN) remains an unmet clinical need. Recent studies suggest that the tumor microenvironment undergoes dynamic changes during PanIN progression. To establish objective pathological markers, this study investigated histological, immunohistochemical, and molecular alterations in PanIN-associated stroma across different grades.
Methods: Fibroblastic cluster (FC) was defined and characterized using immunohistochemistry (IHC) for SMA, CD31, and CD34, and their frequency was assessed according to PanIN grade in 202 PanIN lesions and 58 normal ducts. To identify molecular differences among PanIN types, multiple gene expression analysis (MGEA) was performed for six normal ducts and for three PanIN1, three PanIN2, and six PanIN3 lesions. IHC and fluorescent dual IHC for CD31 and CD36 were performed to quantify CD36-positive stromal vessels. RNA scope for PPARγ and IHC for thrombospondin-1 (TSP-1) and forkhead box O1 (FOXO-1) were performed to explore the molecular basis of CD36 downregulation.
Results: FCs were identified in 86.6% of PanIN3 stroma and were significantly more frequent than in lower-grade PanINs. MGEA revealed downregulation of CD36 in PanIN2-3 compared with PanIN1, and CD36-positive vessels were significantly fewer in higher-grade PanIN stroma. PPARγ signals were present in low-grade but absent in high-grade PanIN stroma. TSP-1 expression paralleled CD36 expression. These findings suggest that the possible relationship between the repression of CD36 in the stromal vasculature of high-grade PanIN and reduced PPARγ and TSP-1 signaling.
Conclusions: Higher-grade PanINs harbor a unique stroma characterized by FC formation and an increased proportion of CD36-negative vessels.
期刊介绍：
Although laboratory and clinical cancer research need to be closely linked, observations at the basic level often remain removed from medical applications. This journal works to accelerate the translation of experimental results into the clinic, and back again into the laboratory for further investigation. The fundamental purpose of this effort is to advance clinically-relevant knowledge of cancer, and improve the outcome of prevention, diagnosis and treatment of malignant disease. The journal publishes significant clinical studies from cancer programs around the world, along with important translational laboratory findings, mini-reviews (invited and submitted) and in-depth discussions of evolving and controversial topics in the oncology arena. A unique feature of the journal is a new section which focuses on rapid peer-review and subsequent publication of short reports of phase 1 and phase 2 clinical cancer trials, with a goal of insuring that high-quality clinical cancer research quickly enters the public domain, regardless of the trial’s ultimate conclusions regarding efficacy or toxicity.
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