Daniel K. Tong

A CD90+ Tumor-Initiating Cell Population with an Aggressive Signature and Metastatic Capacity in Esophageal Cancer

Tumor-initiating cells (TIC), also known as cancer stem cells, are regarded widely as a specific subpopulation of cells needed for cancer initiation and progression. TICs have yet to be identified in esophageal tumors that have an increasing incidence in developed countries. Here, we report a CD90(+) cell population found in esophageal squamous cell carcinoma (ESCC), which is endowed with stem cell-like properties and high tumorigenic and metastatic potential. mRNA profiling of these cells suggested pathways through which they drive tumor growth and metastasis, with deregulation of an Ets-1/MMP signaling pathway and epithelial-mesenchymal transition figuring prominently. These cells possessed higher self-renewal activity and were sufficient for tumor growth, differentiation, metastasis, and chemotherapeutic resistance. CD90(+) TICs were isolated and characterized from ESCC clinical specimens as well as ESCC cell lines. In freshly resected clinical specimens, they represented a rare cell population, the levels of which correlated with strong family histories and lymph node metastasis. Our results prompt further study of this CD90(+) population of esophageal TICs as potential therapeutic targets.

Oxygen carrier YQ23 can enhance the chemotherapeutic drug responses of chemoresistant esophageal tumor xenografts

PurposeAdjunct chemoradiation is offered to unresectable esophageal squamous cell carcinoma (ESCC) patients, while its use is limited in tumors with strong resistance. Oxygen carriers or anti-hypoxic drugs belong to an emerging class of regulators that can alleviate tumor hypoxia.MethodsWe investigate the potential use of a novel oxygen carrier YQ23 in sensitizing chemoresistant ESCC in a series of subcutaneous tumor xenograft models developed using ESCC cell lines with different strengths of chemosensitivities.ResultsTumor xenografts were developed using SLMT-1 and HKESC-2 ESCC cell lines with different strengths of resistance to two chemotherapeutic drugs, 5-fluorouracil and cisplatin. More resistant SLMT-1 xenografts responded better to YQ23 treatment than HKESC-2, as reflected by the induced tumor oxygen level. YQ23 sensitized SLMT-1 xenografts toward 5-fluorouracil via its effect on reducing the level of a hypoxic marker HIF-1α. Furthermore, a derangement of tumor microvessel density and integrity was demonstrated with a concurrent decrease in the level of a tumor mesenchymal marker vimentin. Similar to the 5-fluorouracil sensitizing effect, YQ23 also enhanced the response of SLMT-1 xenografts toward cisplatin by reducing the tumor size and the number of animals with invasive tumors. Chemosensitive HKESC-2 xenografts were irresponsive to combined YQ23 and cisplatin treatment.ConclusionsIn all, YQ23 functions selectively on chemoresistant ESCC xenografts, which implicates its potential use as a chemosensitizing agent for ESCC patients.

Serum microRNA-193b as a promising biomarker for prediction of chemoradiation sensitivity in esophageal squamous cell carcinoma patients

Esophageal squamous cell carcinoma (ESCC) is the most predominantly occurring type of esophageal cancer worldwide. Locally advanced ESCC patients are treated by neoadjuvant chemoradiation for tumor downstaging prior to tumor resection. Patients receiving this treatment have an increased expectation of cure via the following tumor resection and have better survival outcomes. However, not all patients respond well to chemoradiation and poor responders suffer from treatment-associated toxicity and complications without benefits. No method is currently available to predict patient chemoradiation response and to exclude poor responders from ineffective treatment. To address this clinical limitation, the present study aimed to identify non-invasive biomarkers for predicting patient chemoradiation response. Due to the features of microRNA (miRNA) in cancer diagnosis, prognosis and treatment response prediction, serum miRNA arrays were performed to identify potential miRNA(s) that may be used for chemoradiation response prediction in ESCC. Using an miRNA array to compare pre-treatment serum sample pools from 10 good responders and 10 poor responders, the present study identified miR-193b, miR-942 and miR-629* as candidate miRNAs for predicting chemoradiation response. Subsequent validation using reverse transcription-quantitative polymerase chain reaction confirmed that miR-193b, however not miR-942 and miR-629*, were significantly increased in sera from 24 good responders, compared with 23 poor responders. Further analyses using the receiver operating characteristic curve revealed a strong predictive power of serum miR-193b on discriminating good responders from poor responders to chemoradiation. In addition, a high serum level of miR-193b was significantly associated with better survival outcomes. Therefore, serum miR-193b may be considered a promising biomarker for predicting chemoradiation response and post-therapy survival of ESCC patients.

Abstract 3989: MicroRNA-16 and microRNA-193b as serological predictors for chemoradiation response in esophageal squamous cell carcinoma patients

Proceedings: AACR 106th Annual Meeting 2015; April 18-22, 2015; Philadelphia, PA Esophageal cancer is one of the most deadly malignancies along the gastrointestinal tract. Esophageal squamous cell carcinoma (ESCC) is the most common cell type occurring at the upper and middle part of the esophagus. Surgery remains the mainstay treatment for this malignancy, however the long-term prognosis is modest with a 5-year overall survival of approximately 30%. To improve the treatment outcome of this cancer, multimodal treatment strategies including neoadjuvant chemoradiation have been implemented. Such pre-surgery treatment indeed leads to better clinical outcome and increases the chance for cure. Unfortunately patients who do not respond may have to undergo prolonged, unnecessary and potentially toxic treatments with no benefits. Currently, there is no reliable method for chemoradiation response prediction. To address this clinical limitation, we have established a non-invasive assay to stratify chemoradiation responders from non-responders. This study is systematically divided into three phases. In the discovery phase (phase I), we found 23 human microRNAs (out of 742 human microRNAs) with more than 2.5-fold elevation in serum from chemoradiation responders when compared to non-responders. In the selection and small-scale validation phase (phase II), small-scale validation in an independent cohort showed that microRNA-16 and microRNA-193b were two most powerful candidates for indicating chemoradiation responders. In the large-scale validation phase (phase III), we have further validated and confirmed the feasibility of microRNA-16 and miroRNA-193b as discriminators for chemoradiation response in a large cohort of more than a hundred patients. Standard curves were also constructed for these two microRNAs for copy number quantitation. In all, we have newly established a highly sensitive and specific blood-based assay with specific cut-offs for discriminating ESCC patients who are responsive to chemoradiation. This assay works by quantitating the serum level of microRNA-16 and microRNA-193b in ESCC patients, such that patients would be advised to receive pre-surgery chemoradiation if they have elevated levels of circulatory microRNA-16 and microRNA-193b. The development of this assay will benefit patient care by formulating individualized treatment plans. Note: This abstract was not presented at the meeting. Citation Format: Nikki P. Lee, Kenneth K. Lai, Kin Tak Chan, Daniel K. Tong, Simon Law. MicroRNA-16 and microRNA-193b as serological predictors for chemoradiation response in esophageal squamous cell carcinoma patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3989. doi:10.1158/1538-7445.AM2015-3989