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Prostate cancer (PCa) is the second cancer-cause of death of men in the USA. Upon transformation, prostatic epithelial cells (EC) gradually evolve from benign, premalignant, to malignant phenotypes. Prostatic Intraepithelial Neoplasia (PIN) is an abnormal growth of EC progressing from Low grade (L) PIN to High grade (H) PIN. Twenty percent of patients with HPIN advance to PCa, therefore, most studies focus on the HPIN-PCa progression. We hypothesized that the less-studied LPIN stage may feature unique remodeling processes that also predispose to PCa. Perivascular and prostate-resident mast cells (MC) are first-line sources of preformed tumor-promoting mediators, including angiogenic vascular endothelial growth factor-A (VEGF) and sphingosine-1-phosphate (S1P), a sphingolipid metabolite produced by sphingosine kinase (SphK). Using the C3(1)/SV40Tag transgenic (C3) mouse model that mimics human PCa initiation and progression, we sought to investigate remodeling in LPIN. We designed a novel quantitative method of image analysis to measure in situ angiogenesis in prostate sections that integrates capillary-restricted CD31 quantification and morphometric parameters. Increased angiogenesis was discovered in LPIN and MC were located near the newly generated blood capillaries. LPIN sections featured augmented MC numbers, more activated in LPIN, than normal C3 or wild-type littermate sections. Moreover, local mRNA coding for Sphk, Vegfa and matrix metalloproteinase (Mmp) 9 were significantly increased in LPIN samples, accompanied with elevation of S1P. Additional evidence of structural remodeling in LPIN samples included a substantial increase in mRNA coding for collagens type I and III (Col1a1 and Col3a1). Importantly, we established a novel computer-aided imaging method to quantify cell-associated VEGF protein expression in tissue sections based on signal intensity measured through conversion to a gray-scale value then area-under-the-curve calculation. Remarkably, local VEGF expression was exclusively restricted to MC in all experimental groups and was more elevated in LPIN samples. Next, transcriptomics for remodeling genes conducted with human patient samples revealed that, for each patient, cancer-bearing biopsies also featured significant increases in SPHK, VEGF, MMP9, COL1 and COL3 mRNA expressions, compared to normal biopsies. Altogether, our preclinical and human data provides a new strategic paradigm to untangle the link between MC, early local remodeling observed in LPIN and PCa. Surveillance of MC and their mediators may lead to new diagnostic and precision medicine modalities for the clinical targeting of MC and for early interception of PCa. Citation Format: Ahmed Aladhami, Michael Hobensack, Nabihah I. Kumte, Alena P. Chumanevich, Taryn L. Cranford, Alexander Sougiannis, Reilly T. Enos, Kandy T. Velázquez, Ioulia Chatzistamou, John W. Fuseler, Angela Murphy, Carole A. Oskeritzian. Mast cells promote local angiogenic and structural remodeling, a precursor to prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-131.