The epithelial–mesenchymal transition (EMT) plays a critical role in embryonic development. EMT is also involved in cancer progression and metastasis and it is probable that a common molecular ...mechanism is shared by these processes. Cancer cells undergoing EMT can acquire invasive properties and enter the surrounding stroma, resulting in the creation of a favorable microenvironment for cancer progression and metastasis. Furthermore, the acquisition of EMT features has been associated with chemoresistance which could give rise to recurrence and metastasis after standard chemotherapeutic treatment. Thus, EMT could be closely involved in carcinogenesis, invasion, metastasis, recurrence, and chemoresistance. Research into EMT and its role in cancer pathogenesis has progressed rapidly and it is now hypothesized that novel concepts such as cancer stem cells and microRNA could be involved in EMT. However, the involvement of EMT varies greatly among cancer types, and much remains to be learned. In this review, we present recent findings regarding the involvement of EMT in cancer progression and metastasis and provide a perspective from clinical and translational viewpoints. (Cancer Sci 2009)
Intrahepatic cholangiocarcinoma (ICC) is a malignancy that is challenging to treat. Fibroblasts in ICC tissues have been identified as cancer-associated fibroblasts (CAFs) that promote the malignant ...behaviour of ICC cells. An antifibrotic drug nintedanib has been reported to suppress activated hepatic stellate cells in liver fibrosis.
We investigated whether nintedanib could suppress the cancer-promoting effect of CAFs derived from ICC tissues in vitro and in vivo.
CAFs promoted the proliferation and invasion of ICC cells. Nintedanib suppressed activated CAFs expressing α-smooth muscle actin (α-SMA) and inhibited the ICC-promoting effects of CAFs. Nintedanib greatly reduced the levels of cancer-promoting cytokines, such as interleukin (IL)-6 (IL-6) and IL-8, secreted by CAFs. An in vivo study demonstrated that nintedanib reduced xenografted ICC growth and activated CAFs expressing α-SMA, and that combination therapy with nintedanib and gemcitabine against CAFs and ICC cells showed the strongest inhibition of tumour growth compared with the control and single-treatment groups.
Nintedanib inhibited the cancer-promoting effect of CAFs via the suppression of CAF activation and secretion of cancer-promoting cytokines. Our findings suggest that therapeutic strategies combining conventional cytotoxic agents with nintedanib targeting CAFs are promising for overcoming refractory ICC with activated CAFs.
Background
Esophageal neuroendocrine carcinoma (ENEC) has a poor prognosis, and predicting the prognosis by examining various markers may contribute to the determination of treatment strategies. ...Therefore, a multiple-institution retrospective study was performed to identify biomarkers using diagnostic immunohistochemistry and serum tumor markers that predict the prognosis of patients with ENEC.
Methods
The results of immunohistochemical examination and serum tumor markers were extracted from the data of 141 ENEC patients at 39 institutions certified by the Japan Esophageal Society. The study then examined correlations between these data and prognosis or treatment effects.
Results
The ENEC patients with positively for all expression of synaptophysin (Syn), chromogranin A (CgA), and CD56 had a significantly worse prognosis than the patients with other expression patterns. Additionally, surgery and chemoradiotherapy were significantly more effective treatments than chemotherapy for the patients who were not positive for all expressions of Syn, CgA, and CD56. In terms of serum tumor markers, the patients with a high neuron-specific enolase (NSE) value had a significantly worse prognosis than the patients with a normal NSE value, and complete response (CR) cases treated with chemotherapy were significantly fewer in the high-NSE group. The results of multivariate analysis demonstrated that high NSE levels were an independent poor prognostic factor for esophageal endocrine cell carcinoma.
Conclusion
This study showed that positivity for all expressions of Syn, CgA, and CD56, and a high NSE value were significantly worse prognostic factors for ENEC patients than other expression patterns and may be important prognostic biomarkers of ENEC.
Wisteria floribunda agglutinin (WFA)
Mac-2-binding protein (M2BPGi) is a novel serum marker for liver fibrosis. Although an elevated serum level of M2BPGi can predict development of hepatocellular ...carcinoma (HCC), the effect of M2BPGi on HCC remains unclear. There are no reports about the association of M2BPGi with HCC aggressiveness. We aimed to clarify the significance of M2BPGi in HCC.
The protein expression of M2BPGi and galectin-3, a ligand of M2BP, and the mRNA expression of M2BP were evaluated in surgically resected human HCC samples. M2BPGi-regulating signals in HCC cells were investigated using transcriptome analysis. The effects of M2BPGi on HCC properties and galectin-3/mTOR signaling were evaluated.
M2BPGi and galectin-3 proteins co-localised in HCC cells, while M2BP mRNA was detected in cirrhotic liver stromal cells. mTOR signaling was upregulated in M2BPGi-treated HCC cells. Moreover, M2BPGi treatment induced tumour-promoting effects on HCC in vitro by activated mTOR signaling. In addition, M2BPGi bound to galectin-3 to induce membranous galectin-3 expression in HCC cells. In vivo, M2BPGi enhanced the growth of xenografted HCC.
M2BPGi is produced in stromal cells of the cirrhotic liver. Furthermore, M2BPGi enhances the progression of HCC through the galectin-3/mTOR pathway.
L-type amino acid transporter 1 (LAT1), also referred to as SLC7A5, is believed to regulate tumor metabolism and be associated with tumor proliferation. In invasive breast cancer, we ...clinicopathologically investigated the utility of LAT1 expression. LAT1 expression was evaluated via immunohistochemistry analyses in 250 breast cancer patients undergoing long-term follow-up. We assessed the relationships between LAT1 expression and patient outcomes and clinicopathological factors. Breast cancer-specific survival stratified by LAT1 expression was assessed. Human epidermal growth factor receptor 2 (HER2)-positive patients with metastasis received trastuzumab therapy. The density of tumor-infiltrating lymphocytes (TILs) was evaluated according to the International Working Group guidelines. In the current study, high LAT1 expression was significantly correlated with estrogen receptor (ER) negativity, progesterone receptor negativity, high histological grade, increased TILs, and programmed death ligand 1 positivity. Among the ER-positive and HER2-negative patients, high LAT1 was an independent indicator of poor outcomes (hazard ratio (HR) = 2.97; 95% confidence interval (CI), 1.16-7.62; p = 0.023). Moreover, high LAT1 expression was an independent poor prognostic factor in luminal B-like breast cancer with aggressive features (HR = 3.39; 95% CI 1.35-8.52; p = 0.0094). In conclusion, high LAT1 expression could be used to identify a subgroup of invasive breast cancer characterized by aggressive behavior and high tumor immunoreaction. Our findings suggest that LAT1 might be a candidate therapeutic target for breast cancer patients, particularly those with luminal B-like type breast cancer.
Nivolumab, a monoclonal antibody targeting programmed cell death-1, significantly prolongs survival for patients with advanced non-small-cell lung cancer (NSCLC). However, little is known about the ...value of predictive biomarkers. Hence, we investigated the impact of skeletal muscle (SM) mass loss on clinical outcomes in NSCLC patients undergoing nivolumab treatment. Thirty patients with histologically confirmed NSCLC treated with nivolumab were included in this study. Computed tomography was used to determine SM loss based on the SM index (SMI). The SMI is the cross-sectional area of the bilateral psoas muscles at the third lumbar vertebra, divided by height squared. The cut-off values were defined as 6.36 cm/m for men and 3.92 cm/m for women. Among the 30 patients, 13 (43%) had SM loss. There was no significant association between SM loss and immune-related adverse events. The SM loss group had undergone significantly more prior chemotherapy cycles (P = .04). SM loss was significantly associated with fewer nivolumab cycles (P = .01). No patients in the SM loss group achieved a partial response. Patients with SM loss had a significantly shorter progression-free survival period (P = .008) and median overall survival than those with normal SM mass (10 vs 25 months, respectively, P = .03). SM loss was an independent prognostic factor of poor survival. In conclusion, SM loss may be a predictive factor of poor outcomes in NSCLS patients undergoing nivolumab therapy.
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