Lindeman, J. | Search bioRxiv

bioRxiv2024

Whole-Slide ECM Imaging Reveals Dense Fibrous Matrix as a High-Risk Factor for Recurrence in Stage II Colon Cancer

IntroductionThe extracellular matrix (ECM) supports tumor progression by influencing tumor cell migration and invasion. This study examines the link between peritumoral ECM morphology and five-year recurrence risk in TNM Stage II colon cancer, using quantitative whole-slide ECM imaging. We hypothesize that loose ECM regions are associated with increased recurrence risk due to enhanced tumor budding (TB) or poorly differentiated clusters (PDC). MethodsIn a case-control study of 100 TNM Stage II colon cancer patients (25 with recurrence and 75 controls matched by lymph node sampling and tumor extent), Picrosirius red-stained sections were imaged to quantify ten ECM parameters across 798 regions of interest (ROIs). Conditional logistic regression assessed associations between ECM morphologies, TB, PDCs, and recurrence. ResultsUnsupervised clustering identified three ECM morphologies: dense fibrous, loose sparse, and complex tortuous. Dense fibrous ECM correlated strongly with recurrence (aOR 9.43, 95% CI 3.29-29.30, p < 0.001), while loose sparse and complex tortuous ECMs were associated with reduced recurrence risk (aOR 0.33, 95% CI 0.11-0.91, p = 0.040, and aOR 0.14, 95% CI 0.02-0.53, p = 0.012, respectively). TB was highest in loose sparse ECM (mean 9.3), and PDCs were highest in dense fibrous ECM (mean 5.5). DiscussionOur findings suggest that ECM morphology, particularly dense fibrous ECM, predicts recurrence in Stage II colon cancer, highlighting ECM profiling as a promising tool for patient stratification beyond traditional staging.

cancer biology↗

bioRxiv2024

The multifaceted process of human coronary atherosclerotic cap destabilisation

IntroductionPlaque rupture is the primary trigger of the acute clinical manifestations of atherosclerotic disease. So far, factual insight in the processes leading up to cap destabilization is largely missing. In order to overcome this knowledge gap, a pseudo-timeline of atherosclerosis progression was established in order to systematically map the qualitative changes in cap characteristics during lesion progression and destabilization. Material and MethodsA pseudo-timeline was created by randomly selecting preclassified (revised AHA classification, at least 10 per stage) left coronary artery FFPE specimens obtained during tissue donation (aortic valve procurement). Qualitative changes were visualized by (immuno)histochemistry, immunofluorescence and confocal microscopy. Scoring was performed by two observers using semiquantitative scoring estimates. ResultsThe median age of the donors was 56 years (IQR 51.5-59), and 67% of the patients was male. Movat staining indicated a consistent pattern of cap formation, maturation and destabilization. A distinctive cap emerged in the early fibroatheroma stage of progressive atherosclerosis. Disease progression was accompanied by profound fibrotic changes in the gap, and a progressive presence of inanotic (nutritional deprivation leading to dissolution) mesenchymal cells. Plaque rupture was preceded by thinning of the collagen fibers and accumulation of foam cells in the central portion of the thin cap. No evidence was found for a direct involvement of neovascularization in the destabilization process. ConclusionThe pseudo-time line of atherosclerotic lesion development characterizes the development of an unstable cap as a degenerative and fibrotic process with progressive exhaustion of the mesenchymal cell population. This study provides a rationale for the limited efficacy of medical strategies aimed at plaque stabilization.

pathology↗