EGFR mediates docetaxel resistance in human castration-resistant prostate cancer through the Akt-dependent expression of ABCB1 (MDR1).

Recent studies have shown that docetaxel-based chemotherapy confers a survival benefit in patients with castration-resistant prostate cancer (PC). Also epidermal growth factor receptor (EGFR) was found to have multiple roles in prostatic tumorigenesis. However, the EGFR-mediated chemoresistance mechanism in human PC was not well delineated. In this study, we explored the mechanism of EGFR-mediated docetaxel resistance in PC. A series of stable docetaxel-resistant PC/DX sublines were established at our laboratory. The docetaxel IC50s of PC3 and PC/DX25 cells were 0.01 and 1.33 µM, respectively. Cellular resistance to docetaxel was significantly associated with increased EGFR and EGFR activation in PC/DX25. There was a dose-dependent increase in EGFR expression associated with the magnitude of docetaxel resistance. Expression of EGFR in PC/DX25 was higher than that in PC3, RWPE-1 and LNCaP cells. Similar results were also found in human PC tissues by immunohistochemical staining. We showed that docetaxel sensitivity can be stored in PC/DX25 cells by knockdown and inactivation of EGFR expression through EGFR siRNA and specific inhibitors, respectively. Contrarily, overexpression of EGFR or recombinant EGF protein treatment could rescue PC3 cells from docetaxel-mediated cytotoxicity. Gefitninb (ZD1839) significantly inhibited the growth of PC/DX25 cells by MTT in vitro and on xenografted nude mice in vivo. Moreover, EGFR-mediated docetaxel resistance occurred through the Akt-dependent ABCB1 expression in PC cells. These findings demonstrated EGFR played an important role in docetaxel-resistant PC and EGFR inhibition may enhance the therapeutic efficacy of docetaxel-based treatment.

Down-regulation of PKCζ in renal cell carcinoma and its clinicopathological implications.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is highly resistant to systemic chemotherapy. Unfortunately, nearly all patients die of the metastatic and chemoresistant RCC. Recent studies have shown the atypical PKCζ is an important regulator of tumorigenesis. However, the correlation between PKCζ expression and the clinical outcome in RCC patients is unclear. We examined the level of PKCζ expression in human RCC. METHODS: PKCζ mRNA and protein expressions were examined by real-time polymerase chain reaction (PCR) and immunohistochemistry (IHC) respectively in RCC tissues of 144 patients. Cellular cytotoxicity and proliferation were assessed by MTT. RESULTS: PKCζ expression was significantly higher in normal than in cancerous tissues (P<0.0001) by real-time PCR and IHC. Similarly, PKCζ expression was down-regulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. Interestingly, an increase of PKCζ expression was associated with the elevated tumor grade (P=0.04), but no such association was found in TNM stage (P=0.13). Tumors with higher PKCζ expression were associated with tumor size (P=0.048). Expression of higher PKCζ found a poor survival in patients with high tumor grade. Down-regulation of PKCζ showed the significant chemoresistance in RCC cell lines. Inactivation of PKCζ expression enhanced cellular resistance to cisplatin and paclitaxel, and proliferation in HK-2 cells by specific PKCζ siRNA and inhibitor. CONCLUSIONS: PKCζ expression was associated with tumorigenesis and chemoresistance in RCC.

Characterization of membranous and cytoplasmic EGFR expression in human normal renal cortex and renal cell carcinoma.

Metastatic renal cell carcinoma (RCC) is highly resistant to conventional systemic treatments, including chemotherapy, radiotherapy and hormonal therapies. Previous studies have shown over-expression of EGFR is associated with high grade tumors and a worse prognosis. Recent studies suggest anticancer therapies targeting the EGFR pathway have shown promising results in clinical trials of RCC patients. Therefore, characterization of the level and localization of EGFR expression in RCC is important for target-dependent therapy. In this study, we investigated the clinical significance of cellular localization of EGFR in human normal renal cortex and RCC. RCC and adjacent normal kidney tissues of 63 patients were obtained for characterization of EGFR expression. EGFR protein expression was assessed by immunohistochemistry on a scale from 0 to 300 (percentage of positive cells x staining intensity) and Western blotting. EGFR membranous staining was significantly stronger in RCC tumors than in normal tissues (P < 0.001). In contrast, EGFR cytoplasmic staining was significantly higher in normal than in tumor tissues (P < 0.001). The levels of membranous or cytoplasmic EGFR expression in RCC tissues were not correlated with sex, tumor grade, TNM stage or overall survival (P > 0.05). These results showed abundant expression of membranous EGFR in RCC, and abundant expression of cytoplasmic EGFR in normal tissues. EGFR expression in RCC was mostly located in the cell membrane, whereas the EGFR expression in normal renal tissues was chiefly seen in cytoplasm. Our results suggest different locations of EGFR expression may be associated with human renal tumorigenesis.

Downregulation of ABCD1 in human renal cell carcinoma.

Renal cell carcinoma (RCC) is the most common malignant tumor of the kidney. Delayed diagnosis may result in progression and metastasis. Markers for early detection of RCC are lacking. The ATP-binding cassette transporter D1 (ABCD1) is located in the human peroxisome membrane. Its mutation causes X-linked adrenoleukodystrophy (X-ALD), a peroxisomal disorder affecting lipid storage. The role of ABCD1 in human renal tumorigenesis was unclear. In this study, three pairs of RCC tissues were examined by cDNA microarray and data suggested that ABCD1 mRNA is downregulated. Downregulation of ABCD1 expression was confirmed by real-time PCR. ABCD1 expression was also downregulated in four renal cancer cell lines compared to immortalized benign renal tubular cells. ABCD1 mRNA and protein expression levels assessed by immunohistochemistry in the RCC tissues were similar between genders, tumor grades, and tumor stages. Immunohistochemical assays also showed that ABCD1 expression was significantly higher in normal than in cancerous tissues (p<0.001). ABCD1 downregulation may be involved in human renal tumorigenesis.

Down-regulated expression of RhoA in human conventional renal cell carcinoma.

BACKGROUND: Renal cell carcinoma (RCC) is the most common cancer in adult kidney. Delayed diagnosis may result in progression and metastasis. Markers for early detection of RCC are lacking. The small GTPase RhoA has been implicated in the regulation of cell morphology, motility and transformation, but the role of RhoA in tumorigenesis of RCC remains unclear. In this study, the significance of RhoA expression in human RCC was characterized. MATERIALS AND METHODS: RhoA mRNA and protein expressions were examined by real-time polymerase chain reaction (PCR) and immunohistochemistry respectively in 46 pairs of tissues. RESULTS: Real-time PCR revealed that RhoA mRNA expression was significantly lower in cancerous as compared to normal tissues (p = 0.036). RhoA protein expression was significantly higher in normal than in cancerous tissues (p = 0.032). However, RhoA expression did not correlate with age, differentiation grade or TNM stage (all p > 0.05). CONCLUSION: RhoA down-regulation may be involved in human renal tumorigenesis.

Gastro-intestinal metastasis of primary lung carcinoma: clinical presentations and outcome.

Symptomatic gastro-intestinal (GI) metastasis in lung carcinomas is extremely rare and only a few case reports have been published. Here we review all of the cases of lung cancer from January 2003 to April 2005 in a tertiary teaching hospital in Taiwan. A total of six patients (1.77%, 6/339) with primary lung cancer demonstrated symptomatic gastro-intestinal metastasis. Three patients had squamous cell carcinoma, one had adenocarcinoma, and two had small cell carcinoma. Three patients with gastric metastasis were diagnosed via gastro-endoscopy while one with cecal involvement was diagnosed via colon fiberscopy. Two patients with small bowel perforation and intussusception were diagnosed via laparotomy. We presented these rare cases and made a review of the literature.

A case of dermoid cyst ruptured into the lung.

Ruptured cystic teratomas (dermoid cysts) are rare and always symptomatic, presenting as haemothorax, pleural effusion or pericardial effusion. We present an extremely rare case of a 45-year-old woman who, during a routine health assessment was noted to have a well-defined anterior mediastinal tumour with peripheral ground glass opacity on chest CT. The patient was asymptomatic. She underwent video-assisted thoracoscopic surgery and a ruptured dermoid cyst was observed and the contents had infiltrated into the right pulmonary parenchyma. There were no complications and no evidence of recurrence 10 months later. Despite most cystic teratomas being asymptomatic and benign, rupture into the pulmonary parenchyma may induce further damage, for which emergency surgical intervention is always necessary.