Interestingly, the relative concentrations of collagen and glycosaminoglycans (GAGs) appear to alter during disease progression, shifting toward higher GAG content at more advanced and metastatic stages of disease ( Figures 1A–1J). The tight association of this fibrillar collagen with epithelial carcinoma cells became evident in KrasLSL-G12D/+ Trp53LSL-R172H/+ R26LSL-GFP/+ Cre ( KPGC) mice. A robust and definable stromal reaction develops in association with early precursor lesions and includes a dense collagen content organized in a fibrillary structure in both primary tumors and metastases, as revealed by intravital second harmonic generation (SHG) imaging ( Figures S1E–S1J). As part of a systematic effort to characterize the evolving stromal dynamics and potential therapeutic vulnerabilities during disease progression, we performed specific histochemical and immunohistochemical assays to identify components of the ECM and infiltrating cells in preinvasive, invasive, and metastatic PDA in mice and humans ( Figure 1 and Figures S1A–S1D).
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