LOXL2 Is Highly Expressed in Cancer-Associated Fibroblasts and Associates to Poor Colon Cancer Survival

Abstract

Purpose: Cancer-associated fibroblasts (CAF) are major mediators in tumor microenvironment. We investigated the changes in protein expression in colon cancer-associated fibroblasts compared with normal fibroblasts (NF) in the context of searching for prognostic biomarkers, particularly for stage II patients.Experimental Design: CAFs and NFs isolated from colon cancer patients were used to identify differentially expressed proteins using quantitative proteomics. Stromal expression of deregulated proteins was analyzed by IHC. Prognostic impact was studied using external gene-expression datasets for training, then quantitative PCR and IHC for validation in different cohorts of patients. Combined datasets were used for prediction of risk assessment at stages II and III.Results: A desmoplastic signature composed of 32 proteins, highly specific for stromal components in colon cancer, was identified. These proteins were enriched for extracellular matrix organization components, TGFb signaling pathway, fibrosis, and wound-healing proteins. The expression in CAFs of 11 upregulated proteins and four downregulated proteins, selected for biomarker validation, was verified by orthogonal techniques. LOXL2 displayed a high prognostic impact by using external independent datasets and further validation in two different cohorts of patients. High expression of LOXL2 was associated with higher recurrence P ¼ 0. Conclusions: We identified LOXL2 to be associated with the outcome of colon cancer patients. Furthermore, it can be used to stratify patients at stages II and III for further therapeutic decisions.

Lysyl Oxidase Isoforms and Potential Therapeutic Opportunities for Fibrosis and Cancer

“…It is widely over-expressed in cancers, including metastatic cancers. For example, high levels of LOXL2 occur in colon cancer associated fibroblasts 128 , skin cancer 129 , oral cancer 130 , skin and head and neck squamous cell carcinoma 101 , liver metastasis 103 , cholangiocarcinoma 131 , breast cancer 76, 92, 132, 133 , and gastric cancer metastasis 102 . Attenuation of LOXL2 expression was shown to inhibit metastasis or the invasive cell phenotypes in most of these studies.…”

Epidemiological and molecular features of cutaneous squamous cell carcinoma with perineural spread

“…245 Higher expression was also shown to be associated with disease progression in human oesophageal and colon tumours. 246,247 LOXL2 has also become a novel target and a LOXL2 specific monoclonal antibody (AB0023) may find clinical application in cancer, inflammation and fibrosis. 248 LOXL2 may be exerting its actions intracellularly via induction of an EMT phenotype.…”

“…250 LOXL2 may be secreted by stromal cancer-associated fibroblasts or tumour cells. 247,251 LOXL2 secreted by tumour cells has also been shown to activate stromal fibroblasts and cause local desmoplasia (fibrosis), possibly via FAK (focal adhesion kinase) signalling. 199 Increased expression of LOXL2 in stromal fibroblasts has also been shown to be associated with aggressiveness in gastric cancer.…”

“…251 In addition, increased LOXL2 expression in CAFs is associated with reduced OS and increased recurrence in colon cancer patients. 247 The…”

Perineural spread of cutaneous malignancy in a live mouse and ganglion-tumour co-culture model

“…LOXL2 expression is also associated with metastasis in basal like breast carcinomas (50). In colon cancer LOXL2 was found to be highly expressed in cancer-associated fibroblasts and associated with poor survival (51). In the head and neck LOXL2 has been identified as a marker of poor prognosis in laryngeal SCC (52) and is associated with lymph node metastasis and poor outcome in oesophageal SCC (53).…”