Pancreatic cancer has a notoriously poor prognosis, exhibits persistent drug resistance, and lacks a cure. Unique features of the pancreatic tumor microenvironment exacerbate tumorigenesis, metastasis, and therapy resistance. Recent studies emphasize the importance of exploiting cells in the tumor microenvironment to thwart cancers. In this review, we summarize the hallmarks of the multifaceted pancreatic tumor microenvironment, notably pancreatic stellate cells, tumor-associated fibroblasts, macrophages, and neutrophils, in the regulation of chemo-, radio-, immuno-, and targeted therapy resistance in pancreatic cancer. The molecular insight will facilitate the development of novel therapeutics against pancreatic cancer.

<div>Abstract<p><b>Purpose:</b> Mass spectrometry–based biomarker discovery has clinical benefit. To identify novel biomarkers for urothelial carcinoma, we performed quantitative proteomics on pooled urine pairs from patients with and without urothelial carcinoma.</p><p><b>Experimental Design:</b> Shot-gun proteomics using liquid chromatography-tandem mass spectrometry and stable isotope dimethyl labeling identified 219 candidate proteins. The potential implication of SH3 domain binding glutamic acid-rich protein like 3 (SH3BGRL3) was examined by immunoblotting of the urine (<i>n</i> = 13) and urothelial tumors (<i>n</i> = 32). Additional immunohistochemistry was performed on bladder cancer array (<i>n</i> = 1145) and correlated with tumor aggressiveness. Then, biologic functions and signaling pathways of SH3BGRL3 were explored using stable cell lines.</p><p><b>Results:</b> The detectable urine SH3BGRL3 in patients with urothelial carcinoma was positively associated with higher histologic grading and muscle invasiveness of urothelial carcinoma. SH3BGRL3 is expressed in 13.9% (159/1145) of bladder cancer cohort and is positively associated with muscle invasion (<i>P</i> = 0.0028). SH3BGRL3 expression is associated with increased risk of progression in patients with nonmuscle-invasive bladder cancer (<i>P</i> = 0.032). SH3BGRL3 expression is significantly associated with a high level of epidermal growth factor receptor (EGFR) in bladder cancer (<i>P</i> < 0.0001). SH3BGRL3 promotes the epithelial–mesenchymal transition, cell migration, and proliferation of urothelial carcinoma <i>in vitro</i>. SH3BGRL3 interacts with phosphor-EGFR at Y1068, Y1086, and Y1173 through Grb2 by its proline-rich motif, and activates the Akt-associated signaling pathway.</p><p><b>Conclusions:</b> Evaluation of SH3BGRL3 expression status or urine content may identify a subset of patients with bladder cancer who may require more intensive treatment. SH3BGRL3 deserves further investigation as a cotargeting candidate for designing EGFR-based cancer therapies. <i>Clin Cancer Res; 21(24); 5601–11. ©2015 AACR</i>.</p></div>

<p>SH3BGRL3 expression level in uroepithelial cell lines, xenografts and alternation of EMT markers by transient transfection of SH3BGRL3</p>

<p>Co-localization of SH3BGRL3 with EGFR</p>

<p>Protein identification of urine from patients with BPH.</p>