Abstract
Biomarkers and novel therapeutic targets are urgently needed in colorectal cancer (CRC). The pseudo tyrosine kinase receptor 7 (PTK7) is involved in planar cell polarity and it is deregulated in various malignancies, including CRC. Yet, little is known about its protein expression in human CRC, or about a possible correlation of its expression with clinical endpoints. Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined PTK7 expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome. PTK7 depletion by specific shRNA in HCT116 and HCT15 CRC cell lines was found to affect cell proliferation, resistance to drugs and cell migration. Tumor growth and metastatic phenotype were investigated in vivo using a xenograft mouse model of CRC cells with modulated expression of PTK7 levels. PTK7 was significantly up-regulated in CRC tissue as compared to matched healthy mucosae, and significant overexpression was found in 34% of patients. PTK7 overexpression was significantly associated with a reduced metastasis-free survival in non-metastatic patients. In HCT116 and HCT15 cells, shRNA PTK7 reduced migration but did not affect cell proliferation and resistance to drugs. In a xenograft mouse of HCT15 cells, downregulation of PTK7 led to reduced tumor growth, whereas its overexpression in PTK7-negative cancer cells led to increased metastatic events. PTK7 expression thus represents a potential prognostic biomarker and a novel therapeutic target in CRC.
Highlights
With 447 000 cases and 215 000 deaths per year in Europe, colorectal cancer (CRC) remains a major public health issue [1,2]
Using a clinically annotated Tissue MicroArray (TMA) produced from from 192 consecutive CRC patients treated by initial surgery, we examined pseudo tyrosine kinase receptor 7 (PTK7) expression by immunohistochemistry in tumoral tissue and matched normal mucosae, and correlated its expression with clinico-pathological features and patient outcome
In order to better understand the role of PTK7 in colorectal tumorigenesis, we examined its protein expression by immunohistochemistry on a TMA containing tumor tissues from 192 primary CRCs and matched normal mucosa
Summary
With 447 000 cases and 215 000 deaths per year in Europe, colorectal cancer (CRC) remains a major public health issue [1,2]. Integration of 5-FU- and oxaliplatin-based adjuvant chemotherapy to surgical resection in node positive-patients has improved survival [3,4], but a significant number of these patients still relapse and die from metastatic disease. Identification of valid and robust biomarkers that may distinguish a group of patients presenting significant risk of recurrence is urgently needed. Even though some molecular targeted therapeutics have contributed to increase survival in metastatic CRC [6,7,8,9], none of them was demonstrated to improve survival in the adjuvant setting [10,11]. It is still eagerly necessary to identify molecular actors that play a relevant role in colon cancer biology and may serve as targets for novel biological therapies
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