Aligned Collagen Is a Prognostic Signature for Survival in Human Breast Carcinoma

Abstract

Evidence for the potent influence of stromal organization and function on invasion and metastasis of breast tumors is ever growing. We have performed a rigorous examination of the relationship of a tumor-associated collagen signature-3 (TACS-3) to the long-term survival rate of human patients. TACS-3 is characterized by bundles of straightened and aligned collagen fibers that are oriented perpendicular to the tumor boundary. An evaluation of TACS-3 was performed in biopsied tissue sections from 196 patients by second harmonic generation imaging of the backscattered signal generated by collagen. Univariate analysis of a Cox proportional hazard model demonstrated that the presence of TACS-3 was associated with poor disease-specific and disease-free survival, resulting in hazard ratios between 3.0 and 3.9. Furthermore, TACS-3 was confirmed to be an independent prognostic indicator regardless of tumor grade and size, estrogen or progesterone receptor status, human epidermal growth factor receptor-2 status, node status, and tumor subtype. Interestingly, TACS-3 was positively correlated to expression of stromal syndecan-1, a receptor for several extracellular matrix proteins including collagens. Because of the strong statistical evidence for poor survival in patients with TACS, and because the assessment can be performed in routine histopathological samples imaged via second harmonic generation or using picrosirius, we propose that quantifying collagen alignment is a viable, novel paradigm for the prediction of human breast cancer survival.

Periductal stromal collagen topology of pancreatic ductal adenocarcinoma differs from that of normal and chronic pancreatitis

“…Accumulating evidence suggests that focally aligned collagen at the stromacancer interface guides the persistent migration of cancer cells away from the tumor and toward vasculature during the metastatic cascade. 20,[44][45][46] In addition, the detection of aligned collagen signatures in routine histopathology slides can predict disease 16 In pancreatic ductal adenocarcinoma, cancer cells in contact with collagen type I show enhanced migratory capabilities through upregulation of Snail, a regulator of epithelial-to-mesenchymal transition. [47][48][49][50][51] Epithelial-to-mesenchymal transition is a process that dissemination-competent cells undergo.…”

“…61,62 Stromal collagen topology has already been shown to correlate with breast tumors that have a greater propensity to metastasize and negatively impact prognosis. 16 It is likely that a diversity of collagen topology profiles exist in pancreatic ductal adenocarcinoma tumors, which may prove useful as an ancillary disease marker to subtype patients during histological evaluation. It is conceivable that collagen topology could be characterized from tissue obtained preoperatively (via endoscopic fine-needle aspiration or computer tomography-guided core needle biopsy) or post-resection using our validated methodology.…”

The extracellular matrix in breast cancer predicts prognosis through composition, splicing, and crosslinking

“…A dense network of collagen fibers perpendicular to tumor border predicts invasiveness and poorer overall survival [97,98]. In mesenchymal cells, organization of fibriliar matrices is the major determinant of migration patterns, such that cell migration persistence tends to be highest in aligned matrices [97,[99][100][101].…”

Host epithelial geometry regulates breast cancer cell invasiveness

“…The associated changes in ECM stiffness can disrupt normal tissue architecture and induce a malignant phenotype through integrin clustering and activation of ERK (29,43,50). Indeed, alignment of collagen fibrils in the tumor stroma is an independent negative prognostic indicator for human breast carcinomas (51). In addition to these mechanical contributions from the ECM, our data suggest that the mechanical tone (that is, the intrinsic tissue-level contractility or tension) of the surrounding nonmalignant host epithelial tissue may be critical in establishing regions that modulate tumor phenotype.…”