Shixiu Wu

Fractionated irradiation-induced EMT-like phenotype conferred radioresistance in esophageal squamous cell carcinoma

The efficacy of radiotherapy, one major treatment modality for esophageal squamous cell carcinoma (ESCC) is severely attenuated by radioresistance. Epithelial-to-mesenchymal transition (EMT) is a cellular process that determines therapy response and tumor progression. However, whether EMT is induced by ionizing radiation and involved in tumor radioresistance has been less studied in ESCC. Using multiple fractionated irradiation, the radioresistant esophageal squamous cancer cell line KYSE-150R had been established from its parental cell line KYSE-150. We found KYSE-150R displayed a significant EMT phenotype with an elongated spindle shape and down-regulated epithelial marker E-cadherin and up-regulated mesenchymal marker N-cadherin in comparison with KYSE-150. Furthermore, KYSE-150R also possessed some stemness-like properties characterized by density-dependent growth promotion and strong capability for sphere formation and tumorigenesis in NOD-SCID mice. Mechanical studies have revealed that WISP1, a secreted matricellular protein, is highly expressed in KYSE-150R and mediates EMT-associated radioresistance both in ESCC cells and in xenograft tumor models. Moreover, WISP1 has been demonstrated to be closely associated with the EMT phenotype observed in ESCC patients and to be an independent prognosis factor of ESCC patients treated with radiotherapy. Our study highlighted WISP1 as an attractive target to reverse EMT-associated radioresistance in ESCC and can be used as an independent prognostic factor of patients treated with radiotherapy.

Cancer-associated fibroblasts mediated chemoresistance by a FOXO1/TGFβ1 signaling loop in esophageal squamous cell carcinoma.

Previous studies on the mechanisms underlying ESCC (esophageal squamous cell carcinoma) chemoresistance only focused on tumor cells while tumor microenvironment has been completely ignored. Our study aimed to clarify the effect of CAFs (cancer‐associated fibroblasts), one major component of tumor microenvironment, on the chemoresistance of ESCC. By primary culture, two pairs of CAFs and matched NFs (normal fibroblasts) were isolated from tumor tissues of ESCC patients and matched normal esophageal epithelial tissues, respectively. The association of CAFs and chemoresistance was assessed in esophageal carcinoma cells, in xenograft tumor models and in clinical specimens of ESCC patients. We found CAFs conferred ESCC cells significant resistance to several common chemotherapeutic drugs including cisplatin, taxol, irinotecan (CPT‐11), 5‐fluorouracil (5‐Fu), carboplatin, docetaxel, pharmorubicin, and vincristine. Mechanism studies revealed that blockage of CAFs‐secreted TGFβ1 signaling by its receptor TGFβR1 inhibitor LY2157299 significantly reversed the chemoresistance in vitro and in vivo. Furthermore, the crosstalk of CAFs and ESCC cells enhanced the expression and activation of FOXO1, a member of the forkhead transcription factors in the O‐box sub‐family, inducing TGFβ1 expression in an autocrine/paracrine signaling loop. In 130 ESCC patients, the expression of TGFβ1 in CAFs was significantly associated with overall survival of patients treated with chemoradiotherapy. Together, our study highlighted TGFβ1 expressed in CAFs as an attractive target to reverse tumor chemoresistance, and can be used as an independent prognostic factor of ESCC patients treated with chemoradiotherapy.

Subsequent treatment choices for patients with acquired resistance to EGFR-TKIs in non-small cell lung cancer: restore after a drug holiday or switch to another EGFR-TKI?

The outcomes of first-generation EGFR-TKIs (Gefitnib and Erlotinib) have shown great advantages over traditional treatment strategies in patients with non-small cell lung cancer (NSCLC), but unfortunately we have to face the situation that most patients still fail to respond in the long term despite initially good control. Up to now, the mechanism of acquired resistance to EGFR-TKIs has not been fully clarified. Herein, we sought to compile the available clinical reports in the hope to better understanding the subsequent treatment choices, particularly on whether restoring after a drug holiday or switching to another EGFR-TKI is the better option after failure of one kind of EGFR-TKI.

XRCC3 Polymorphisms are Associated with the Risk of Developing Radiation-induced Late Xerostomia in Nasopharyngeal Carcinoma Patients Treated with Intensity Modulation Radiated Therapy

OBJECTIVE The incidence of radiation-induced late xerostomia varies greatly in nasopharyngeal carcinoma patients treated with radiotherapy. The single-nucleotide polymorphisms in genes involved in DNA repair and fibroblast proliferation may be correlated with such variability. The purpose of this paper was to evaluate the association between the risk of developing radiation-induced late xerostomia and four genetic polymorphisms: TGFβ1 C-509T, TGFβ1 T869C, XRCC3 722C>T and ATM 5557G>A in nasopharyngeal carcinoma patients treated with Intensity Modulation Radiated Therapy. METHODS The severity of late xerostomia was assessed using a patient self-reported validated xerostomia questionnaire. Polymerase chain reaction-ligation detection reaction methods were performed to determine individual genetic polymorphism. The development of radiation-induced xerostomia associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for equivalent uniform dose. RESULTS A total of 43 (41.7%) patients experienced radiation-induced late xerostomia. Univariate Cox proportional hazard analyses showed a higher risk of late xerostomia for patients with XRCC3 722 TT/CT alleles. In multivariate analysis adjusted for clinical and dosimetric factors, XRCC3 722C>T polymorphisms remained a significant factor for higher risk of late xerostomia. CONCLUSIONS To our knowledge, this is the first study that demonstrated an association between genetic polymorphisms and the risk of radiation-induced late xerostomia in nasopharyngeal carcinoma patients treated with Intensity Modulation Radiated Therapy. Our findings suggest that the polymorphisms in XRCC3 are significantly associated with the risk of developing radiation-induced late xerostomia.

CAF-secreted CXCL1 conferred radioresistance by regulating DNA damage response in a ROS-dependent manner in esophageal squamous cell carcinoma

Five-year survival rate of esophageal squamous cell carcinoma (ESCC) patients treated with radiotherapy is <20%. Our study aimed to investigate whether cancer-associated fibroblasts (CAFs), one major component of tumor microenvironment, were involved in tumor radioresistance in ESCC. By use of human chemokine/cytokine array, human chemokine CXCL1 was found to be highly expressed in CAFs compared with that in matched normal fibroblasts. Inhibition of CXCL1 expression in CAFs significantly reversed CAF-conferred radioresistance in vitro and in vivo. CAF-secreted CXCL1 inhibited the expression of reactive oxygen species (ROS)-scavenging enzyme superoxide dismutase 1, leading to increased ROS accumulation following radiation, by which DNA damage repair was enhanced and the radioresistance was mediated. CAF-secreted CXCL1 mediated the radioresistance also by activation of Mek/Erk pathway. The cross talk of CAFs and ESCC cells induced CXCL1 expression in an autocrine/paracrine signaling loop, which further enhanced tumor radioresistance. Together, our study highlighted CAF-secreted CXCL1 as an attractive target to reverse tumor radioresistance and can be used as an independent prognostic factor of ESCC patients treated with chemoradiotherapy.

Prognostic Nomogram for Patients with Nasopharyngeal Carcinoma after Intensity-Modulated Radiotherapy

This study was aimed to define possible predictors of overall survival in nasopharyngeal carcinoma (NPC). Patients were treated with intensity-modulated radiation therapy (IMRT), to establish an effective prognostic nomogram that could provide individualized predictions of treatment outcome in this setting. We reviewed the records of 533 patients with non-metastatic NPC who underwent IMRT with or without concurrent chemotherapy at the Department of Radiation Oncology of Sun Yat-Sen University from 2002 to 2009; none of these patients received induction or adjuvant chemotherapy. These data sets were used to construct a nomogram based on Cox regression. Nomogram performance was determined via a concordance index (C-index) and a calibration curve which was compared with the TNM staging system for NPC. The results were validated in an external cohort of 442 patients from the Department of Radiation Oncology of Wenzhou Medical College who were treated during the same period. Results showed that the greatest influence on survival were primary gross tumor volume, age, tumor stage and nodal stage (2002 Union for International Cancer Control [UICC] staging system), which were selected into the nomogram. The C-index of the nomogram for predicting survival was 0.748 (95%CI, 0.704–0.785), which was statistically higher than that of TNM staging system (0.684, P<0.001). The calibration curve exhibited agreement between nomogram-predicted and the actual observed probabilities for overall survival. In the validation cohort, the nomogram discrimination was superior to the TNM staging system (C-index: 0.768 vs 0.721; P = 0.026). In conclusion, the nomogram proposed in this study resulted in more-accurate prognostic prediction for patients with NPC after IMRT and compared favorably to the TNM staging system; this individualized information will aid in patient counseling and may be used for de-escalation trials in the future.

Stereotactic body radiation therapy and thymosin alpha-1-induced anti-tumor effects in heavily pretreated, metastatic esophageal squamous cell carcinoma patients

ABSTRACT This study investigated the anti-tumor effects of stereotactic body radiation therapy (SBRT) with thymosin alpha-1 (Tα1) in heavily pretreated, metastatic esophageal squamous cell carcinoma (mESCC) patients. Thirty-one patients with at least 2 metastatic sites were enrolled. SBRT was delivered with a daily fraction of 5.0 Gy for a total dosage of 25 Gy over one week to one metastatic lesion. Concurrent Tα1 (1.6mg subcutaneously) was administered twice a week with an interval of 3-4 days until tumor progression of other documented metastatic lesions. Anti-tumor effects (the primary endpoint) were evaluated by assessing the CT/MRI response of other distinct measurable lesions. Secondary endpoints included treatment safety, survival outcomes and immune-related blood parameters. This study was registered at ClinicalTrials.gov (NCT 02545751). Partial response occurred in three (9.7%) patients, and 11 (35.5%) patients had stable metastatic disease, which yielded a metastatic-lesion control rate of 45.2%. Seventeen (54.8%) patients were documented to have progressive disease in other metastatic lesions. The median overall survival and abscopal progression free survival (APFS) times were 5.2 and 2.9 months, respectively. Significant differences in survival outcomes were observed between the abscopal control group (without progression in the abscopal lesions at 12 weeks) and the non-control group (P = 0.035 and 0.044, respectively). Treatment-related toxicity was acceptable, and no grade 4 acute toxicity occurred. Immunomonitoring of lymphocytes showed that the proportion of CD8+ T cells after treatment was significantly different between the abscopal control group and the non-control group (P=0.047). In conclusion, the combination of SBRT with Tα1 produced encouraging effects in heavily pretreated, mESCC patients and further research on radiation enhanced immunotherapy is warranted.

High-sensitivity modified Glasgow prognostic score (HS-mGPS) Is superior to the mGPS in esophageal cancer patients treated with chemoradiotherapy

The present study compared the prognostic value of the modified Glasgow prognostic score (mGPS) and high-sensitivity mGPS (HS-mGPS) in unresectable locally advanced esophageal squamous cell carcimona (LAESCC) patients treated with concurrent chemoradiotherapy (CCRT). The baseline data of 163 eligible patients were retrospectively collected. Patients with a C-reactive protein (CRP) ≤ 10 mg/l and albumin ≥ 35 g/l were allocated to mGPS-0 group. Patients with only elevated CRP (> 10 mg/l) were assigned to mGPS-1 group. Patients who had both elevated CRP (> 10 mg/l) and hypoalbuminurea (< 35 g/l) were assigned to mGPS-2 group. The HS-mGPS was calculated based on cutoff values of 3mg/l for CRP and the same value (35 g/l) for albumin. Prognostic significance for both tumor response and overall survival (OS) was analyzed by univariate and multivariate analysis. The mGPS was 0 in 95 patients, 1 in 28 patient and 2 in 40 patients. In contrast, the HS-mGPS was 0 in 66 patients, 1 in 47 patients and 2 in 50 patients. In multivariate analysis, the HS-mGPS was the only positive factor for tumor response (P = 0.015). Both the mGPS (P < 0.001) and HS-mGPS (P < 0.001) were good prognostic predictors for OS. However, the HS-mGPS was found to be a superior prognostic predictor compared to the mGPS in a multivariate analysis (P = 0.006). In conclusion, the pretreatment HS-mGPS is a strong prognosticator superior to the mGPS for both tumor response and OS in LAESCC patients who received CCRT.

Long-term outcome of concurrent chemoradiotherapy with elective nodal irradiation for inoperable esophageal cancer

Elective nodal irradiation (ENI) might improve overall survival in patients with inoperable esophageal cancer. We conducted a retrospective analysis to assess the long‐term survival and toxicity of esophageal cancer patients treated with ENI versus conventional‐field irradiation (CFI). All data in the present study were based on our institutional experience from 2000 to 2005 of patients with inoperable esophageal cancer treated with ENI or CFI plus two concurrent cycles of paclitaxel/cisplatin. Based on the inclusion and exclusion criteria, 89 patients were included in the analysis. Of these patients, 51 were treated with ENI, whereas 38 were treated with CFI. For the per‐protocol population, the patients in the ENI group significantly improved in terms of their 10‐year disease‐specific overall survival (43.1% vs 10.5%, P = 0.019), 10‐year disease‐free survival (36.7% vs 10.2%, P = 0.040) and 10‐year local recurrence‐free survival (47.2% vs 17.2%, P = 0.018) compared with the CFI group. Aside from radiation esophagitis, the incidence of grade 3 or greater acute toxicities did not differ between the two groups. Multivariate analysis showed that radiation field, tumor length and clinical stage were independent prognostic factors associated with OS. Concurrent chemoradiotherapy with ENI improves both disease‐specific overall survival and loco‐regional control in patients with inoperable esophageal cancer receiving per‐protocol treatment. The regimen has a manageable tolerability profile.