Original contributionTropomyosin receptor kinases B and C are tumor progressive and metastatic marker in colorectal carcinoma☆
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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Role of Tropomyosin-related kinase B receptor and brain-derived neurotrophic factor in cancer
2020, CytokineCitation Excerpt :After binding the growth factor with TrkB, this receptor auto-phosphorylates, initiating a downstream cascade leading to cell proliferation, differentiation, and growth as seen in Fig. 1 [4]. Some studies show that the NTRK family can act as an oncogene in several human malignant tumors [6,7], and the TrkB receptor has been associated with neuroblastoma [7], Wilm’s tumor [8], prostate cancer [8], hepatocellular carcinoma [9], pancreatic cancer [10], ovarian cancer [11], gastric cancer [12,13], head and neck squamous cells carcinoma (HNSCC) [14], colon cancer [15–17], oral squamous cells carcinoma, and breast cancer [18]. The overexpression of TrkB and BDNF is associated with a poor prognosis in cancer as it plays a role in the formation of metastasis and mesenchymal epithelial transition (EMT) [19,20], invasion, migration, and proliferative activities [21].
Expression and clinical significance of TrkB in sinonasal squamous cell carcinoma: a pilot study
2017, International Journal of Oral and Maxillofacial SurgeryCitation Excerpt :Therefore, it is suspected that a significant relationship between TrkB expression levels and lymph node metastasis may be established with the analysis of a larger number of samples. Several studies have reported that TrkB may promote invasion and metastasis.17,20 Therefore, TrkB may contribute to the progression and metastasis of malignant tumours.
Entrectinib is a potent inhibitor of Trk-driven neuroblastomas in a xenograft mouse model
2016, Cancer LettersCitation Excerpt :Indeed, of 11 patients enrolled across both clinical trials who demonstrated presence of NTRK1/2/3, ROS1 or ALK fusions and were treated at or above the recommended phase 2 dose, 10 achieved objective clinical response, yielding an overall response rate of 91% in this population, and 9 of these patients remained in the study with durable responses up to 16 cycles of treatment [52,53]. There is evidence for TRK expression, alteration, and/or autocrine activation in many other pediatric and adult cancers, including Wilms tumor [54], medulloblastoma [55–58], Ewing sarcoma [59], infantile fibrosarcoma [60–62], breast cancer [63–69], prostate cancer [70–74], colorectal cancer [38,75–80], pancreatic cancer [81–85], lung cancer [86–89] and others. Suppression of TRK expression in these tumors has shown similar effects on cell growth and metastatic potential, and entrectinib has specifically been tested in both colorectal cancer and non-small-cell lung cancer [37,38,42,52,53,75–77,86].
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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.