Distinctive Responsiveness to Stromal Signaling Accompanies Histologic Grade Programming of Cancer Cells

摘要: Abstract Whether stromal components facilitate growth, invasion, and dissemination of cancer cells or suppress neoplastic lesions from further malignant progression is a continuing conundrum in tumor biology. Conceptualizing dynamic picture tumorigenesis complicated by inter-individual heterogeneity. In the post genomic era, unraveling such complexity remains challenge for biologist. Towards establishing functional association between cellular crosstalk differential aggressiveness, we identified signature breast epithelial response to signaling. Proximity fibroblasts resulted gene transcript alterations >2-fold 107 probes, collectively designated as Fibroblast Triggered Gene Expression Tumor (FTExT). The hazard ratio predicted FTExT classifier distant relapse patients with intermediate high grade tumors was significant compared routine clinical variables (dataset 1, n = 258, HR--2.11, 95% CI 1.17-3.80, p-value 0.01; dataset 2, 171, HR--3.07, 1.21-7.83, 0.01). Biofunctions represented included inflammatory signaling, free radical scavenging, cell death, proliferation. Unlike genes 'proliferation cluster', which are overexpressed aggressive primary tumors, were uniquely repressed cases. As proof concept our correlative findings, link stromal-epithelial behavior, show distinctive impact on prognosis-defining endpoints cycle progression, resistance therapy-induced growth arrest apoptosis low vs. cells. Our experimental data thus reveal aspects 'paracrine cooperativity' that exclusively contingent upon histopathologically defined interacting epithelium, demonstrate responsiveness microenvironment deterministic factor underlying outcome. this light, early attenuation epithelial-stromal could improve management cases prone be clinically challenging.