Abstract
Cell–cell and cell–matrix adhesion proteins that have been implicated in colorectal epithelial integrity and epithelial‐to‐mesenchymal transition could be robust prognostic and potential predictive biomarkers for standard and novel therapies. We analyzed in situ protein expression of E‐cadherin (ECAD), integrin β4 (ITGB4), zonula occludens 1 (ZO‐1), and cytokeratins in a single‐hospital series of Norwegian patients with colorectal cancer (CRC) stages I–IV (n = 922) using multiplex fluorescence‐based immunohistochemistry (mfIHC) on tissue microarrays. Pharmacoproteomic associations were explored in 35 CRC cell lines annotated with drug sensitivity data on > 400 approved and investigational drugs. ECAD, ITGB4, and ZO‐1 were positively associated with survival, while cytokeratins were negatively associated with survival. Only ECAD showed independent prognostic value in multivariable Cox models. Clinical and molecular associations for ECAD were technically validated on a different mfIHC platform, and the prognostic value was validated in another Norwegian series (n = 798). In preclinical models, low and high ECAD expression differentially associated with sensitivity to topoisomerase, aurora, and HSP90 inhibitors, and EGFR inhibitors. E‐cadherin protein expression is a robust prognostic biomarker with potential clinical utility in CRC.
Highlights
Epithelial cancers, the carcinomas, make up over 80% of cancer cases and deaths, where the majority of cancer patients die from metastatic disease [1]
The expressions of epithelial cell–cell adhesion and polarity markers were assessed in the Norwegian colorectal cancer (CRC) series 1 (TMA1; n = 922, 689 evaluable cases, Table S2) by quantitative fluorescent multiplex immunohistochemistry of zona occludens 1 (ZO-1), integrin b4 (ITGB4), ECAD, and cytokeratins (PanCK) (Fig. 2)
In welldifferentiated and polarized epithelium, the hemidesmosome-associated ITGB4 was localized to the basal membrane of the epithelial islands, whereas in higher grade tumors with invading structures, it had lost its membrane localization and appeared more in the cytoplasm
Summary
Epithelial cancers, the carcinomas, make up over 80% of cancer cases and deaths, where the majority of cancer patients die from metastatic disease [1]. Systemic treatment is primarily based on 5-fluorouracil (5-FU) in combination regimens with oxaliplatin or irinotecan or as monotherapy, while biologically targeted therapies are offered in the metastatic setting mainly with VEGF inhibition, or biomarker guided for tumors that are KRAS/NRAS wild-type (anti-EGFR therapy), have BRAF V600E mutation (BRAF inhibitor) [6] or are microsatellite instable (immune checkpoint therapy) [7]. For the majority of patients, few biomarkers exist to guide oncological intervention, either for systemic chemotherapy or for other targeted therapies such as anti-VEGF therapy or treatment with the multikinase inhibitor regorafenib. There is an unmet need for clinically useful prognostic and predictive biomarkers for this purpose
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