Elsevier

Human Pathology

Volume 44, Issue 6, June 2013, Pages 1098-1106
Human Pathology

Original contribution
Tropomyosin receptor kinases B and C are tumor progressive and metastatic marker in colorectal carcinoma

https://doi.org/10.1016/j.humpath.2012.09.016Get rights and content

Summary

Members of the tropomyosin receptor kinase (Trk) family have a high affinity for neurotrophins and regulate neuronal survival. The role of Trks in cancer is still controversial. The expression and role of TrkB and TrkC were examined in colorectal cancer (CRC). Immunohistochemical analysis of TrkB and TrkC was performed in 133 patients with CRC. Using human CRC cell lines, expression of vascular endothelial growth factor (VEGF) and transforming growth factor β, cell growth, invasion, and apoptosis were examined by knockdown methods. Immunohistochemistry showed positive results of TrkB and TrkC (23.3% and 12.8%, respectively). TrkB expression was associated with local progression (P = .0284), clinical stage (P = .0026), nodal metastasis (P = .0068), and peritoneal metastasis (P = .0026). TrkC expression was only related to liver metastasis (P = .0001). Coexpression of TrkB or TrkC and their ligands was found in 80.6% and 82.4% of cases, respectively. In vitro analysis using human CRC cells showed that TrkB positively regulated gene expression of VEGF-A (P < .05) and VEGF-C (P < .05), whereas TrkC suppressed transforming growth factor β expression (P < .05). TrkB and TrkC induced cell growth (P < .05) and invasion (P < .05), respectively. Both TrkB and TrkC showed antiapoptotic effect (P < .05). These results suggest that TrkB and TrkC have a tumor progressive function and may be a useful diagnostic and therapeutic target in CRC.

Introduction

Colorectal cancer (CRC) is the third most common malignancy worldwide [1] and is responsible for more than 500 000 deaths annually [2]. The overall 5-year survival rate decreases from approximately 80% in patients without nodal metastases to 50% in patients with nodal metastasis [3]; it is less than 10% in those with distant metastasis [4]. Liver metastasis is found in 30% to 60% of metastatic cases, and most patients who have liver metastases die within 5 years of diagnosis [5]. Therefore, early detection of CRC is important, and elucidation of the detailed molecular mechanism promoting metastasis of CRC is critical.

Ligands for the tropomyosin receptor kinase (Trk) family are neurotrophins (NTs); TrkA binds to nerve growth factor, TrkB binds to brain-derived neurotrophic factor (BDNF) and NT-4/5, and TrkC binds to NT-3 [6], [7]. NTs initiate autophosphorylation at the extracellular domain of Trks by binding to Trks and promoting downstream signaling transduction pathways [7]. The Trk family has been reported as regulating neuronal survival and differentiation [8]. Trks also act as oncogenes; TrkA overexpression has been observed in thyroid carcinoma [9], [10]. Higher expression levels of TrkB have been found in many tumors and are associated with more aggressive tumor behavior [11], [12]. In CRC, TrkC directly binds to the bone morphogenetic protein type II receptor and inhibits bone morphogenetic protein signaling [13]. Moreover, TrkB and TrkC inhibit apoptosis in ovarian cancer and neuroblastoma cells via phosphatidylinositol 3′-kinase (PI3K)–AKT signaling, respectively [14], [15]. However, it has been reported that TrkB expression is down-regulated in prostate cancer [16]. Furthermore, TrkC plays an favorable role in medulloblastoma, leading to a good clinical outcome [17], and cases of neuroblastoma with high expression of TrkA or TrkC have a better prognosis [18], [19]; thus, the role of Trks in tumors is still controversial.

It has been reported recently that TrkB induces angiogenesis by activation of vascular endothelial growth factor (VEGF)-A in neuroblastoma [20] and that TrkC suppresses transforming growth factor (TGF) β signaling in breast cancer [21]. We also confirmed that TrkB and TrkC promote tumor progression, nodal metastasis, and induction of angiogenesis and lymphangiogenesis in oral cancer [22]; however, not much information is available about the expression pattern and clinicopathologic significance of Trks in CRC. In this study, we examined the expression of TrkB/C and the effects on the VEGF family and TGF-β signaling by using clinical samples and cell lines of CRC.

Section snippets

Tissue samples

Formalin-fixed, paraffin-embedded 133 cases of primary CRCs (92 men and 41 woman; age range, 48-79 years; means, 68.7 years), and 9 fresh-frozen specimens each of CRC and noncancerous colorectal mucosa were randomly selected from Nara Medical University Hospital, Kashihara, Japan, and Miyoshi General Hospital, Miyoshi, Japan. All cases received no preoperative treatment. Tumor staging and the histology of CRCs were classified according to TNM classification and World Health Organization

Expression of Trks in patients with CRC

At first, we performed immunohistochemistry analysis of TrkB and TrkC in 133 patients with CRC. Expression of TrkB (Fig. 1A) and TrkC (Fig. 1B) was negative or very weak in nontumoral colorectal mucosa; immunoreactivity of TrkB (Fig. 1C) and TrkC (Fig. 1D) was localized to the cytoplasm of CRC cells. Of the 133 patients with CRC, expression of TrkB and TrkC was found in 31 (23.3%) and 17 (12.8%) patients, respectively. The relationship between expression of TrkB or TrkC and clinicopathologic

Discussion

Trks have high affinity for NTs; they regulate the survival and differentiation of developmental neurons and maintain growth and action of neuronal synapses throughout adulthood [28]. Trks are regarded as oncogenes [11], [12], [13], [14], [15], [20], [21], and we recently found that TrkB and TrkC have tumor progression functions in oral squamous cell carcinoma [22]. However, it has been reported that Trks have tumor suppression functions; thus, the role of Trks in cancer remains controversial.

Acknowledgment

This work was supported, in part, by Grant-in-Aid for Scientific Research from Japan Society for the Promotion of Science, Japan.

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    Conflict of interest statement: We declare that there is no financial support or any relationships that may pose a conflict of interest in the contents of the submitted manuscript.

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