Cancer‐associated stroma reveals prognostic biomarkers and novel insights into the tumour microenvironment of colorectal cancer and colorectal liver metastases

BACKGROUND AND AIMS: Cancer‐associated stroma (CAS) is emerging as a key determinant of metastasis in colorectal cancer (CRC); however, little is known about CAS in colorectal liver metastases (CRLM). This study aimed to validate the prognostic significance of stromal protein biomarkers in primary CRC and CRLM. Secondly, this study aimed to describe the transcriptome of the CAS of CRLM and identify novel targetable pathways of metastasis. METHODS: A case–control study design from a prospectively maintained database was adopted. The prognostic value of epithelial and stromal CALD1, IGFBP7, POSTN, FAP, TGF‐β and pSMAD2 expression was assessed by immunohistochemistry (IHC) in multivariate models. Pathway enrichment and sparse partial least square‐discriminant analysis (sPLS‐DA) were performed on a nested cohort after isolating epithelial tumour and CAS by laser capture microdissection. RESULTS: 110 CRCs with 124 paired CRLMs, and 110 matched non‐metastatic control CRCs were included. Median follow‐up was 62 and 45 months for primary and CRLM groups, respectively. Stromal FAP and POSTN were independent predictors for the development of CRLM. After CRLM resection, stromal IGFBP7 and POSTN were predictors of poorer survival. sPLS‐DA on the nested cohort identified a number of novel targetable stromal genes and pathways that defined poor prognosis CRC and the CAS of CRLM. CONCLUSIONS: This study is the first to describe key differences in stromal gene expression between paired primary CRC and CRLM as well as identifying several targetable biomarkers and transcriptomic pathways whose relevance specifically in the CAS of CRC and CRLM have not been previously described.