Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection

Abstract

Risk factors for pancreatic ductal adenocarcinoma (PDAC) progression after surgery are unclear, and additional prognostic factors are needed to inform treatment regimens and therapeutic targets. PDAC is characterized by advanced sclerosis of the extracellular matrix, and interactions between cancer cells, fibrillar collagen, and other stromal components play an integral role in progression. Changes in stromal collagen alignment have been shown to modulate cancer cell behavior and have important clinical value in other cancer types, but little is known about its role in PDAC and prognostic value. We hypothesized that the alignment of collagen is associated with PDAC patient survival. To address this, pathology-confirmed tissues from 114 PDAC patients that underwent curative-intent surgery were retrospectively imaged with Second Harmonic Generation (SHG) microscopy, quantified with fiber segmentation algorithms, and correlated to patient survival. The same tissue regions were analyzed for epithelial-to-mesenchymal (EMT), α-SMA, and syndecan-1 using complimentary immunohistostaining and visualization techniques. Significant inter-tumoral variation in collagen alignment was found, and notably high collagen alignment was observed in 12% of the patient cohort. Stratification of patients according to collagen alignment revealed that high alignment is an independent negative factor following PDAC resection (p = 0.0153, multivariate). We also found that epithelial expression of EMT and the stromal expression of α-SMA and syndecan-1 were positively correlated with collagen alignment. In summary, stromal collagen alignment may provide additional, clinically-relevant information about PDAC tumors and underscores the importance of stroma-cancer interactions.

Clinical value of serum hyaluronan and propeptide of type III collagen in patients with pancreatic cancer

“…HA and collagen accumulation increase tumor solid stress and interstitial fluid pressure (IFP), compromising blood vessels, circulation, perfusion and drug penetration . The prognostic value of HA and collagen deposition in PC tissue has been described in a few studies . HA was hypothesized to be a potential therapeutic target to decrease tumor IFP and enhance drug delivery and immune cells’ access into the tumor .…”

Methods for Quantifying Fibrillar Collagen Alignment

“…The development of this program was driven by our active work in characterizing the role of collagen organization in disease [4–10, 31, 38–45]. This software platform uses two fiber analysis methods, CT-FIRE [38] and curvelets fiber representation (CFR) [25].…”

“…This enabled Drifka and colleagues to determine that stromal collagen alignment is significantly higher in pancreatic cancer compared to normal and chronic pancreatitis tissue [9]. Moreover, it was discovered that the degree of collagen alignment in pancreatic tumors correlates with patient survival [10]. A demonstration of CurveAlign in CT-FIRE mode, without a boundary for both a full image and ROI-based analysis, in pancreatic tissue [9] is shown in Fig.…”

Pancreatic cancer: a mechanobiology approach

“…This also involves integrin mechanosignalling that amplifies epidermal growth factor receptor (EGFR) dependent PI3 kinase (PI3K) signalling [16]. Furthermore, the periductal collagen in PDAC exhibits architectural and structural differences in terms of linearization, alignment, and thickness, which can serve as an independent prognostic factor but might also facilitate cancer invasion through topographical contact guidance [27,28]. New imaging modalities such as second harmonic generation (SHG) imaging and elastography enable visualisation of cell-matrix interactions in 3D environments (in vitro) [29] and assessment of mechanical properties of tissues (in vivo) [30] and will help advance our understanding how structural, topographical, and mechanical changes of the microenviron ment can impact cancer cell behaviour.…”