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ABSTRACT: The epithelial-mesenchymal transition (EMT) is a key mechanism in both embryonic development and cancer metastasis. The EMT introduces stem-like properties to cancer cells. However, during somatic cell reprogramming, mesenchymal-epithelial transition (MET), the reverse process of EMT, is a crucial step toward pluripotency. Connective tissue growth factor (CTGF) is a multi-functional secreted protein that acts as either an oncoprotein or a tumor suppressor among different cancers. Here, we demonstrate that in head and neck squamous cell carcinoma (HNSCC), CTGF promotes the MET and reduces invasiveness. Moreover, we found that CTGF enhances the stem-like properties of HNSCC cells and increases the expression of multiple pluripotency genes. Mechanistic studies showed that CTGF induces c-Jun expression through αvβ3 integrin and that c-Jun directly activates the transcription of the pluripotency genes NANOG, SOX2, and POU5F1. Knockdown of CTGF in TW2.6 cells was shown to reduce tumor formation and attenuate E-cadherin expression in xenotransplanted tumors. In HNSCC patient samples, CTGF expression was positively correlated with the levels of CDH1, NANOG, SOX2, and POU5F1. Co-expression of CTGF and the pluripotency genes was found to be associated with a worse prognosis. These findings are valuable in elucidating the interplay between epithelial plasticity and stem-like properties during cancer progression and provide useful information for developing a novel classification system and therapeutic strategies for HNSCC.
Cancer Research 05/2013; · 7.86 Impact Factor
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ABSTRACT: Observation or elective neck dissection (END) for cN0 neck remains controversial for the treatment of T1-2 oral squamous cell carcinoma (OSCC). Perineural invasion (PNI) has been recognized as a poor prognostic factor for OSCC. However, its significance in T1 OSCC remains unclear. A detailed histologic reevaluation of PNI was carried out in 307 patients with T1-2 OSCC who received surgical treatment between June 2001 and January 2009. We found that the presence of PNI correlated with cervical lymph node metastasis in both T1 and T2 OSCC, with a lower PNI-positive rate in T1 (17.1% vs. 36.6%; P<0.001). Importantly, observation for cN0 neck was used twice as often in T1 than in T2 patients (47.4% vs. 22.8%; P<0.001). Although patients with T1 OSCC achieved significantly better outcomes, PNI correlated with neck recurrence and poor disease-specific survival (DSS) only in T1 (P<0.001 and P<0.0001) but not in T2 patients (P=0.399 and 0.1478). Of the 146 patients with T1 OSCC, PNI independently predicted cervical lymph node metastasis, neck recurrence, and poor DSS. END significantly reduced neck recurrence of T1 OSCC in PNI-positive (P=0.001) but not in PNI-negative (P=0.114) patients. In addition, END improved the 5-year DSS of T1 OSCC more in PNI-positive than in PNI-negative patients (16.2% vs. 5.4%). Our results indicate that PNI independently predicts a poor prognosis in T1 OSCC patients who are potentially curable but tend to be treated conservatively. For its efficacy in improving treatment outcomes, aggressive END is indicated for T1 OSCC patients at the presence of PNI.
The American journal of surgical pathology 05/2013; · 4.06 Impact Factor
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ABSTRACT: The optimal treatment for tonsillar squamous cell carcinoma (SCC) remains controversial. The purpose of this study was to evaluate long-term treatment outcomes of patients with tonsillar SCC, in order to aid in appropriate treatment selection.
We conducted a retrospective chart review of 105 patients with curatively treated tonsillar SCC between January 1996 and December 2005. Forty-three patients (41.0%) underwent primary surgery with or without adjuvant therapy (primary surgery group), and 62 patients (59.0%) were treated with radiotherapy/chemoradiotherapy (RT/CRT, organ preservation group). Twenty patients (19%) received tumor tonsillectomy before definitive RT/CRT and were grouped into the organ preservation group.
No significant differences were observed between the primary surgery and organ preservation groups in terms of local control (p = 0.212), regional control (p = 0.684), distant metastasis (p = 0.627), 5-year disease-specific survival (DSS, p = 0.774), and overall survival rates (OS, p = 0.667). The rates of major complication (p = 0.216), long-term dependency on feeding tubes (p = 0.876), and tracheostomy (p = 0.401) were also similar. Advanced T classification (T3-4) was the only factor associated with significantly worse DSS (p = 0.007) and OS (p = 0.012). However, there was also no difference in final treatment outcomes in T3-4 patients regardless of whether they were treated with primary surgery or RT/CRT. In the organ preservation group, tumor tonsillectomy before RT/CRT did not improve local control (p = 0.520) or other treatment outcomes, including 5-year DSS (p = 0.707) and OS (p = 0.745).
Both primary surgery and RT/CRT organ preservation are effective treatments for tonsillar SCC. Single modality treatment, either surgery or RT/CRT, can typically be provided for stage I-II diseases. Although RT/CRT organ preservation is used more frequently for stage III-IV tonsillar SCC in recent years, primary surgery combined with adjuvant therapy still achieves equivalent outcomes. Multidisciplinary pretreatment counseling and the facilities and personnel available are therefore important for decision-making. In addition, if RT/CRT organ preservation is selected as the primary treatment, tumor tonsillectomy is not indicated.
Journal of the Chinese Medical Association 04/2013; 76(4):211-7. · 0.79 Impact Factor
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ABSTRACT: OBJECTIVE: Carotid blowout syndrome is a severe complication of head and neck cancer. High mortality and major neurologic morbidity are associated with carotid blowout syndrome with massive bleeding. Prediction of outcomes for carotid blowout syndrome patients is important for clinicians, especially for patients with the risk of massive bleeding. METHODS: Between 1 January 2001 and 31 December 2011, 103 patients with carotid blowout syndrome were enrolled in this study. The patients were divided into groups with and without massive bleeding. Prognostic factors were analysed with proportional hazard (Cox) regressions for carotid blowout syndrome-related prognoses. Survival analyses were based on the time from diagnosis of carotid blowout syndrome to massive bleeding and death. RESULTS: Patients with massive bleeding were more likely to have hypoalbuminemia (albumin <3.5 g/dl; P = 0.023). Univariate analysis of carotid blowout syndrome-related massive bleeding showed that treatment for carotid blowout syndrome (best supportive care, P = 0.000; embolization, P = 0.000), monocytosis (monocytes >1000 cells/μl, P = 0.041) and hypoalbuminemia (P = 0.010) were important to prognosis. Concurrent chemoradiotherapy (P = 0.007), elevated lactate dehydrogenase (>250 U/l; P = 0.050), local recurrence (P = 0.022) and hypoalbuminemia (P = 0.038) were related to poor prognosis in carotid blowout syndrome-related death. In multivariate analysis, best supportive care and hypoalbuminemia were independent factors for both carotid blowout syndrome-related massive bleeding (P = 0.000) and carotid blowout syndrome-related death (P = 0.013), respectively. CONCLUSION: Best supportive care and serum albumin are important prognostic factors in carotid blowout syndrome. It helps clinicians to evaluate and provide better supportive care for these patients.
Japanese Journal of Clinical Oncology 03/2013; · 1.78 Impact Factor
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ABSTRACT: The movement modes of epithelial cancer cells in three-dimensional (3D) environments include the mesenchymal mode, which is associated with local invasion, and the amoeboid mode, which facilitates distant metastasis. The migratory behavior of individual cancer cells is critical for tumor dissemination; however, the mechanism underlying regulation of the switch between movement modes is not clearly understood. For head and neck squamous cell carcinoma (HNSCC), local invasion is the major route of dissemination. We previously demonstrated that, in HNSCC cells, Twist1 represses let-7i expression to elicit mesenchymal-mode movement through activation of Ras-related C3 botulinum toxin substrate 1 (RAC1). In this study, we discover another important target gene of let-7i for regulating HNSCC migration. Using bioinformatic tools, we identified bone morphogenetic protein 4 (BMP4) as a candidate target of let-7i. Further experiments, including 3'-untranslated region (UTR) reporter assays, quantitative RT-PCR and western blotting, confirmed that BMP4 is a bona fide target repressed by let-7i. In the HNSCC cell line OECM-1, knockdown of BMP4 reduced mesenchymal-mode migration and invasion in 3D culture. In clinical HNSCC samples, let-7i expression was inversely correlated with BMP4 expression. Our results revealed that let-7i attenuates mesenchymal-mode migration of HNSCC cells through repression of a novel target, BMP4.
Biochemical and Biophysical Research Communications 02/2013; · 2.48 Impact Factor
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ABSTRACT: Chromosomal instability (CIN) is widely considered a hallmark of cancer but its precise roles in cancer stem cells (CSCs) and malignant progression remain uncertain. BMI1 is a member of the Polycomb group of chromatin modifier proteins that is essential for stem cell self-renewal. In human cancers, BMI1 overexpression drives stem-like properties associated with induction of epithelial-mesenchymal transition (EMT) that promotes invasion, metastasis and poor prognosis. Here we report that BMI1 mediates its diverse effects through upregulatiion of the mitotic kinase Aurora A which is encoded by the AURKA gene. Two mechanisms were found to be responsible for BMI1-induced AURKA expression. First, BMI1 activated the Akt pathway, thereby upregulating AURKA expression through activation of the β-catenin/TCF4 transcription factor complex. Second, BMI1 repressed microRNA let-7i through a Polycomb complex-dependent mechanism, thereby relieving AURKA expression from let-7i suppression. AURKA upregulation by BMI1 exert several effects, including centrosomal amplification and aneuploidy, anti-apoptosis and cell cycle progression through p53 degradation and EMT through stabilization of Snail. Inhibiting aurora A kinase activity attenuated BMI1-induced tumor growth in vivo. In clinical specimens of head and neck cancer, we found that co-amplification of BMI1 and AURKA correlated with poorer prognosis. Together, our results link CSCs, EMT and CIN through the BMI1-AURKA axis and suggest therapeutic utility from inhibiting Aurora A in head and neck cancers which overexpress BMI1.
Cancer Research 11/2012; · 7.86 Impact Factor
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ABSTRACT: BACKGROUND: Lymphoid stroma is a specific pathologic appearance in gastric cancer. This study aims to compare the clinicopathological characteristics of gastric cancer patients with and without lymphoid stroma. METHODS: From January 1988 to February 2009, 222 out of 1,959 patients with lymphoid stroma of gastric cancer received gastrectomy at the Department of Surgery, Taipei Veterans General Hospital. Clinicopathological characteristics and survival rates were analyzed and compared among the gastric cancer patients with and without lymphoid stroma. For patients with lymphoid stroma, CD20 expression of B lymphocytes and CD3 expression of T lymphocytes were examined using immunohistochemical stains. RESULTS: Advanced gastric cancer patients with lymphoid stroma had better 5-year survival status than those without lymphoid stroma (44.5% vs. 20.5%, P < 0.001). Univariate and multivariate analyses showed that male gender (P = 0.034), tumor invasion depth (P = 0.001), pathological staging (P = 0.006), and Ming's histological classification (P = 0.041) were significantly correlated with patients with lymphoid stroma. B lymphocytes appeared more in Borrmann type III and IV, diffuse Lauren's histological type, and lymph nodes metastases. CONCLUSION: Advanced gastric cancer patients with lymphoid stroma had better prognosis than those without lymphoid stroma. B lymphocytes appeared more in aggressive gastric cancer tissues with lymphoid stroma. J. Surg. Oncol © 2012 Wiley Periodicals, Inc.
Journal of Surgical Oncology 10/2012; · 2.10 Impact Factor
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Chih-Yuan Chung,
Sheng-Fung Lin,
Po-Min Chen,
Ming-Chih Chang,
Woei-You Kao,
Tsu-Yi Chao,
Liang-Tsai Hsiao,
Chuen-Chuan Yen, Muh-Hwa Yang,
Wei-Shou Hwang,
Tung-Liang Lin,
Tzeon-Jye Chiou,
Cheng-Shyong Chang
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ABSTRACT: Thalidomide inhibits angiogenesis and exerts complex immunomodulatory activities. This phase II study aimed to examine the efficacy of thalidomide in Taiwanese patients with myelodysplastic syndrome (MDS).
Sixty patients [intention to treat group (ITT)] with MDS were treated with thalidomide (100 mg/day, increased by 100 mg/day weekly to a maximum of 400 mg/day) for 12 weeks. Forty-two patients of the ITT group were considered as comprising the evaluable population (EP).
Thalidomide resulted in hematological improvement (HI) in 28% of ITT analysis and in HI in 40% of the EP. Thalidomide was more effective for MDS patients with low to intermediate-1 International Prognostic Score System scores. The response rates were 7% for ITT and 10% for EP patients. Only two patients exhibited a cytogenetic response. Net reduced levels of vascular endothelial growth factor and basic fibroblast growth factor cytokines were observed in the peripheral blood and the bone marrow of thalidomide-treated patients.
Low-dose thalidomide is an effective and safe treatment for patients with low-risk MDS.
Anticancer research 08/2012; 32(8):3415-9. · 1.73 Impact Factor
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Hsueh-Ju Lu,
Kuo-Wei Chen,
Cheng-Hwai Tzeng,
Jin-Hwang Liu,
Tzeon-Jye Chiou,
Chueh-Chuan Yen,
Ta-Chung Chao,
Hao-Wei Teng,
Ming-Huang Chen,
Chun-Yu Liu,
Wei-Shu Wang,
Peter Mu-Hsin Chang, Muh-Hwa Yang
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ABSTRACT: Carcinoma of unknown origin has a poor outcome and usually occurs in elderly patients. In this article, we analyzed the prognostic factors in elderly patients with cancer of unknown primary site (CUP) for treatment considerations.
Patients >70 years old with histologically proven carcinoma were retrospectively reviewed. The prognostic factors were analyzed with univariate and multivariate Cox regression.
We included 63 patients aged 70-79 years and 51 patients ≥80 years old. The results of multivariate Cox regression in the 70-79 years age group revealed white blood cell count ≤10(4)/ml [p = 0.033; hazard ratio (HR) 2.51, range 1.079-5.840] and albumin ≥3.5 g/dl (p = 0.007; HR 3.38, range 1.398-8.177) as independent factors. In the group of patients ≥80 years old, Eastern Cooperative Oncology Group performance status <1 (p = 0.020), white blood cell count ≤10(4)/ml (p = 0.001), albumin ≥3.5 g/dl (p = 0.006), lactate dehydrogenase (LDH) ≤250 U/l (p = 0.002) and non-chest metastasis (p = 0.043) were significantly better with univariate analysis. Multivariate Cox regression revealed albumin ≥3.5 g/dl (p = 0.007; HR 3.28, range 1.389-7.745) and LDH ≤250 U/l (p = 0.045; HR 3.18, range 1.026-9.848) as independent factors.
For elderly patients with CUP, the serum albumin level seems to be a consistently independent prognostic factor. In patients >80 years old, serum LDH plays an important role in prognosis. This study is helpful in predicting the outcome and management for this group of patients.
Oncology 06/2012; 83(1):24-30. · 2.27 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT), which is characterized by the suppression of the adhesion protein E-cadherin, is a crucial process that promotes metastasis and stem-like properties of cancer cells. However, the dissociation of cellular aggregates is not sufficient to explain why cancer cells move, and the motile nature of cancer cells undergoing EMT remains elusive. Here, we identify a mechanism in which the EMT inducer Twist1 elicits cancer cell movement through activation of RAC1. Twist1 cooperates with BMI1 to suppress let-7i expression, which results in upregulation of NEDD9 and DOCK3, leading to RAC1 activation and enabling mesenchymal-mode movement in three-dimensional environments. Moreover, the suppression of let-7i contributes to Twist1-induced stem-like properties. Clinically, activation of the Twist1-let-7i-NEDD9 axis in head and neck cancer patients correlates with tumour invasiveness and worse outcome. Our results uncover an essential mechanism to explain how Twist1 induces the motile stem-like cancer cell phenotype beyond simply suppressing E-cadherin.
Nature Cell Biology 03/2012; 14(4):366-74. · 19.49 Impact Factor
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Kuo-Wei Chen,
Chia-Jen Liu,
Hsueh-Ju Lu,
Cheng-Hwai Tzeng,
Jin-Hwang Liu,
Tzeon-Jye Chiou,
Chueh-Chuan Yen,
Wei-Shu Wang,
Ta-Chung Chao,
Hao-Wei Teng,
Ming-Huang Chen,
Chun-Yu Liu,
Peter Mh Chang, Muh-Hwa Yang
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ABSTRACT: Carcinoma of unknown primary site (CUP) has a poor prognosis and the prognostic factors in these patients are not well established. Furthermore, there are no selection criteria for patients who should benefit from chemotherapy.
The medical records of 179 CUP patients who were treated at Taipei Veterans General Hospital from 2000 to 2009 were reviewed. Factors associated with survival were determined by Kaplan-Meier analysis. Differences between the groups with and without palliative chemotherapy were analyzed.
Univariate analysis revealed multiple prognostic factors, including performance status, lung metastasis, number of metastatic organs, serum albumin, corrected serum calcium, lactate dehydrogenase (LDH), sodium, and cholesterol levels, palliative chemotherapy, and white blood cell and lymphocyte counts. Multivariate analysis showed that performance status < 2, serum albumin level ≥ 3.5 g/dl, corrected serum calcium level < 10.7 mg/dl, single metastatic organ, and palliative chemotherapy were independent factors of better prognosis. Patients with better performance status, higher serum albumin, and lower serum LDH levels had significantly greater benefit from palliative chemotherapy.
Certain patients with unfavorable CUP will have better survival. Identification of patients with unfavorable CUP who could benefit from palliative chemotherapy warrants future prospective studies.
BMC Research Notes 01/2012; 5:70.
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ABSTRACT: Although perineural invasion (PNI) has been a poor prognostic factor for head and neck cancers, few studies have focused on oral squamous cell carcinoma (OSCC). The independent significance of PNI in early T1-2 OSCC and the benefit of treatment modification based on PNI status have not been assessed. This study investigated the role of PNI in T1-2 OSCC patients, with focus on the controversial issues of neck management and postoperative adjuvant therapy.
PNI status was re-reviewed under hematoxylin and eosin staining in tumors of 307 consecutive T1-2 OSCC patients. Oncologic and survival outcomes were analyzed by univariate and multivariate analyses.
PNI was identified in 84 (27.4%) patients, correlating with several established poor prognostic factors. In multivariate analysis, PNI remained an independent predictor for neck metastasis, neck recurrence, and a worse 5-year disease-specific survival. Elective neck dissection contributed to a significantly better 5-year disease-specific survival only in cN0 patients with PNI-positive tumors (P = 0.0071) but not in those with PNI-negative tumors (P = 0.3566). In low-risk patients who were treated by surgery alone, including neck dissection, the 5-year disease-specific survival rates were almost the same in those with PNI-positive tumors and those with PNI-negative tumors (92.0 vs. 92.9%; P = 0.9104).
Elective neck dissection is indicated for cN0 patients with PNI-positive tumors for the efficacy of improving disease-specific survival as well as neck control. However, low-risk PNI-positive patients who undergo neck dissection do not need postoperative adjuvant therapy, because the residual risk from PNI is minimal.
Annals of Surgical Oncology 12/2011; 19(6):1995-2002. · 4.17 Impact Factor
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ABSTRACT: EMT (epithelial-mesenchymal transition), a major mechanism of cancer metastasis, is a process that generates cells with stem-like properties. These stem-like cells in tumours are described as cancer stem cells. The link between EMT and cancer stemness is well documented without detailed mechanistic proof. Bmi1 belongs to the PRC1 (polycomb repressive complex 1) maintaining self-renewal and stemness together with EZH2 (enhancer of zeste homologue 2), which is a component of PRC2. Bmi1 is frequently overexpressed in different types of human cancers. Recent demonstration of an EMT regulator, Twist1, directly regulating the expression of Bmi1 provides a mechanistic explanation of the relationship between EMT and cancer stemness. The functional interdependence between Twist1 and Bmi1 provides a fresh insight into the common mechanism mediating EMT and cancer stemness. This observation is also confirmed using head and neck cancer patient samples. These results provide a critical mechanism of Twist1-induced EMT and cancer stemness in cancer cells through chromatin remodelling. The role of hypoxia and microRNAs in regulating EMT and cancer stemness is also discussed.
Bioscience Reports 12/2011; 31(6):449-55. · 2.38 Impact Factor
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ABSTRACT: This retrospective study was to establish a prognostic scoring system for patients with non-metastatic head and neck squamous cell carcinoma (HNSCC).
The medical records of 151 patients with HNSCC were evaluated. Clinical data were collected and statistical analyses were performed to determine the prognostic value of pretreatment variables and to build a risk stratification system. Analysis of the data for 94 additional patients validated the risk stratification system.
Three independent adverse prognostic factors were identified: Age <65 years, LDH ≥ upper normal limit and performance status. The risk stratification was defined as two or more adverse factors presented at diagnosis versus one adverse factor or no adverse factors. Patients with two or more adverse factors had a shorter survival regardless of treatment. This was confirmed in both the training set and the validation set.
This risk stratification provides additional information to the current tumor staging system, which could be useful in making decisions for individual patients and selecting more homogenous patients when designing clinical trials.
Journal of the Chinese Medical Association 11/2011; 74(11):487-92. · 0.79 Impact Factor
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ABSTRACT: Epithelial-mesenchymal transition (EMT) is important for organ development, metastasis, cancer stemness, and organ fibrosis. Molecular mechanisms to coordinately regulate hypoxia-induced EMT remain elusive. Here, we show that HIF-1α-induced histone deacetylase 3 (hdac3) is essential for hypoxia-induced EMT and metastatic phenotypes. Change of specific chromatin states is associated with hypoxia-induced EMT. Under hypoxia, HDAC3 interacts with hypoxia-induced WDR5, recruits the histone methyltransferase (HMT) complex to increase histone H3 lysine 4 (H3K4)-specific HMT activity, and activates mesenchymal gene expression. HDAC3 also serves as an essential corepressor to repress epithelial gene expression. Knockdown of WDR5 abolishes mesenchymal gene activation but not epithelial gene repression during hypoxia. These results indicate that hypoxia induces different chromatin modifiers to coordinately regulate EMT through distinct mechanisms.
Molecular cell 09/2011; 43(5):811-22. · 14.61 Impact Factor
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ABSTRACT: To reduce severe acute and late toxicities without compromising organ preservation survival in patients with locoregionally advanced head and neck squamous cell carcinoma, we performed three-drug induction methotrexate-cisplatin-fluorouracil with weekly cisplatin-fluorouracil concurrent chemoradiation.
Two induction courses of methotrexate (40 mg/m(2)/day, days 1, 8 and 15), cisplatin and 5-fluorouracil (25 and 750 mg/m(2)/day, days 1-4) were given in new diagnoses of patients with non-nasopharyngeal locoregionally advanced head and neck squamous cell carcinoma. Responders received concurrent chemoradiation with weekly cisplatin (20 mg/m(2)/day) and 5-fluorouracil (400 mg/m(2)/day) on day 1.
Among 57 patients (58% with Stage IV and hypopharyngeal cancer), the rates of Grade 3-4 toxicity were 30 and 74% during induction and CCRT, respectively. A total of 49 patients completed induction and began concurrent chemoradiation; 47 (96%) completed all planned treatment. With a median follow-up of 62 months (range 19-83 months) for the current survivors, the 3-year overall and disease-specific survival estimates were 50 and 58%, respectively. The 3-year organ preservation survival was 74% in patients who achieved complete remission after concurrent chemoradiation, and 96% of current survivors are tracheotomy and feeding tube-free. No patient without local/regional failure suffered from distant metastasis.
Methotrexate-cisplatin-fluorouracil induction chemotherapy followed by weekly cisplatin-fluorouracil concurrent chemoradiation is an acute and late toxicity-acceptable protocol without attenuating organ preservation survival in patients with locoregionally advanced head and neck squamous cell carcinoma. In this patient cohort with advanced head and neck squamous cell carcinoma, overall and organ preservation survivals were encouraging, and provided promising long-term benefits of this approach.
Japanese Journal of Clinical Oncology 08/2011; 41(10):1182-93. · 1.78 Impact Factor
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Wei-Lun Hwang, Muh-Hwa Yang,
Ming-Long Tsai,
Hsin-Yi Lan,
Shu-Han Su,
Shih-Ching Chang,
Hao-Wei Teng,
Shung-Haur Yang,
Yuan-Tzu Lan,
Shih-Hwa Chiou,
Hsei-Wei Wang
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ABSTRACT: Some cancer cells have activities that are similar to those of stem cells from normal tissues, and cell dedifferentiation correlates with poor prognosis. Little is known about the mechanisms that regulate the stem cell-like features of cancer cells; we investigated genes associated with stem cell-like features of colorectal cancer (CRC) cells.
We isolated colonospheres from primary CRC tissues and cell lines and characterized their gene expression patterns by microarray analysis. We also investigated the biological features of the colonosphere cells.
Expanded CRC colonospheres contained cells that expressed high levels of CD44 and CD166, which are markers of colon cancer stem cells, and had many features of cancer stem cells, including chemoresistance and radioresistance, the ability to initiate tumor formation, and activation of epithelial-mesenchymal transition (EMT). SNAIL, an activator of EMT, was expressed at high levels by CRC colonospheres. Overexpression of Snail in CRC cells induced most properties of colonospheres, including cell dedifferentiation. Two hundred twenty-seven SNAIL-activated genes were up-regulated in colonospheres; gene regulatory networks centered around interleukin (IL)-8 and JUN. Blocking IL-8 expression or activity disrupted SNAIL-induced stem cell-like features of colonospheres. We observed that SNAIL activated the expression of IL8 by direct binding to its E3/E4 E-boxes. In CRC tissues, SNAIL and IL-8 were coexpressed with the stem cell marker CD44 but not with CD133 or CD24.
In human CRC tissues, SNAIL regulates expression of IL-8 and other genes to induce cancer stem cell activities. Strategies that disrupt this pathway might be developed to block tumor formation by cancer stem cells.
Gastroenterology 04/2011; 141(1):279-91, 291.e1-5. · 11.68 Impact Factor
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ABSTRACT: To test the efficacy and safety of a triweekly reduced-dose docetaxel (60 mg/m(2)) regimen combined with a standard dose of cisplatin in patients with recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC).
Patients with R/M HNSCC were enrolled. All eligible patients received intravenous docetaxel 60 mg/m(2) combined with cisplatin 75 mg/m(2) on day 1 and then every 3 weeks thereafter. Treatment was continued until disease progression, patient intolerance, or death.
In total, 58 patients were enrolled and 41 patients were evaluated. Among the evaluated population, one patient achieved a complete response (2.4%) and nine patients achieved a partial response (22%), resulting in an overall response rate of 24.4%. Furthermore, 17 patients had stable disease (41.5%), which corresponds to a disease control rate of 65.9%. With a median follow-up of 24 months (1-43 months), progression-free survival was 170 days (95% confidence interval 97.9-242.1) and the median overall survival was 265 days (95% confidence interval 89.0-441.0) in evaluable population. The most common toxicities (≥ grade III) were leucopenia (66.7%) and anemia (33.3%).
Triweekly reduced-dose docetaxel 60 mg/m(2) combined with cisplatin is effective and feasible for Taiwanese patients with R/M HNSCC. However, the hematologic toxicity of this regimen should be carefully monitored and managed.
Cancer Chemotherapy and Pharmacology 04/2011; 68(6):1477-84. · 2.83 Impact Factor
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ABSTRACT: To investigate the efficacy and safety of combination therapy with ifosfamide and etoposide in cisplatin-refractory recurrent/metastatic squamous cell carcinoma of the head and neck.
Thirty patients with cisplatin-refractory recurrent/metastatic squamous cell carcinoma of the head and neck were treated with ifosfamide (1000 mg/m(2)/day) as a continuous 24 h infusion for 3 days and etoposide (100 mg/m(2)/day) as a bolus 1 h infusion on the same 3 days. The treatment was repeated every 4 weeks until disease progression.
The overall rate of response was 27% (8/30), and 20% (6/30) of the patients achieved stable disease status. Median overall survival was 7.7 months. Subgroup analysis demonstrated significant improvement in overall survival in the group that achieved control of disease. Thirteen (43.3%) patients developed grade 3-4 neutropenia, and five (16.6%) developed grade 3-4 non-hematologic mucositis.
This combination chemotherapy had an effective and safe profile and improved survival in patients with cisplatin-refractory recurrent/metastatic squamous cell carcinoma of the head and neck who achieved disease control.
Japanese Journal of Clinical Oncology 02/2011; 41(5):630-6. · 1.78 Impact Factor
