International Journal of Cancer

The AKT2 gene is one of the human homologues of v‐akt, the transduced oncogene of the AKT8 virus, which induces lymphomas in mice. In previous studies, AKT2, which codes for a serine‐threonine protein kinase, was shown to be amplified and overexpressed in some human ovarian carcinoma cell lines and amplified in primary tumors of the ovary. To confirm and extend these findings, we conducted a large‐scale, multicenter study of AKT2 alterations in ovarian and breast cancer. Southern‐blot analysis demonstrated AKT2 amplification in 16 of 132 (12.1%) ovarian carcinomas and in 3 of 106 (2.8%) breast carcinomas. No AKT2 alteration was detected in 24 benign or borderline tumors. Northern‐blot analysis revealed overexpression of AKT2 in 3 of 25 fresh ovarian carcinomas which were negative for AKT2 amplification. The difference in the incidence of AKT2 alterations in ovarian and breast cancer suggests a specific role for this gene in ovarian oncogenesis. No significant association was found between AKT2 amplification and amplification of the proto‐oncogenes MYC and ERBB2, suggesting that amplification of AKT2 defines an independent subset of breast and ovarian cancers. Ovarian cancer patients with AKT2 alterations appear to have a poor prognosis. Amplification of AKT2 was especially frequent in undifferentiated tumors (4 of 8, p = 0.019), suggesting that AKT2 alterations may be associated with tumor aggressiveness. © 1995 Wiley‐Liss, Inc.

We derived from blood lymphocytes of a melanoma patient a large number of cytolytic T‐cell clones directed against a cell line of the autologous tumor. Three distinct groups of antigens were recognized by these CTL on the autologous melanoma cells: group A consisted of stable antigens present on all sublines, whereas antigens B and C appeared unstable and were expressed by distinct sublines. In vitro immunoselec‐tions with various anti‐A CTL clones were applied to the melanoma cells and variants resistant to 3 different CTL clones were obtained. These variants remained sensitive to other anti‐A CTL clones, indicating that group A comprises at least 4 different antigens (D, E, F and A). From a total of 76 CTL clones obtained from lymphocytes collected from the patient at various times, we found that 45 were anti‐B, 17 were anti‐C, 2 were anti‐D, 9 were anti‐E, 2 were anti‐F and I was anti‐A′. It is therefore likely that the 6 antigens identified by these CTL clones represent all or nearly all the transplantation antigens recognized by autologous CTL on this human melanoma.

Các ước tính về tỷ lệ mắc và tử vong do 27 loại ung thư chính và tổng hợp cho tất cả ung thư trong năm 2012 hiện đã có sẵn trong series GLOBOCAN của Cơ quan Nghiên cứu Ung thư Quốc tế. Chúng tôi xem xét các nguồn và phương pháp đã sử dụng để biên soạn các ước tính tỷ lệ mắc và tử vong do ung thư ở từng quốc gia, và mô tả ngắn gọn các kết quả chính theo vị trí ung thư và trong 20 “khu vực” lớn trên thế giới. Tổng cộng, có 14,1 triệu trường hợp mới và 8,2 triệu ca tử vong trong năm 2012. Những loại ung thư được chẩn đoán phổ biến nhất là ung thư phổi (1,82 triệu), ung thư vú (1,67 triệu) và ung thư đại trực tràng (1,36 triệu); những nguyên nhân phổ biến nhất gây tử vong do ung thư là ung thư phổi (1,6 triệu ca tử vong), ung thư gan (745.000 ca tử vong) và ung thư dạ dày (723.000 ca tử vong).

The “Warburg effect,” also termed aerobic glycolysis, describes the increased reliance of cancer cells on glycolysis for ATP production, even in the presence of oxygen. Consequently, there is continued interest in inhibitors of glycolysis as cancer therapeutics. One example is dichloroacetate (DCA), a pyruvate mimetic that stimulates oxidative phosphorylation through inhibition of pyruvate dehydrogenase kinase. In this study, the mechanistic basis for DCA anti‐cancer activity was re‐evaluated in vitro using biochemical, cellular and proteomic approaches. Results demonstrated that DCA is relatively inactive (IC₅₀ ≥ 17 mM, 48 hr), induces apoptosis only at high concentrations (≥25 mM, 48 hr) and is not cancer cell selective. Subsequent 2D‐PAGE proteomic analysis confirmed DCA‐induced growth suppression without apoptosis induction. Furthermore, DCA depolarizes mitochondria and promotes reactive oxygen species (ROS) generation in all cell types. However, DCA was found to have selective activity against rho(0) cells [mitochondrial DNA (mtDNA) deficient] and to synergize with 2‐deoxyglucose in complex IV deficient HCT116 p53(−/−) cells. DCA also synergized in vitro with cisplatin and topotecan, two antineoplastic agents known to damage mitochondrial DNA. These data suggest that in cells “hardwired” to selectively utilize glycolysis for ATP generation (e.g., through mtDNA mutations), the ability of DCA to force oxidative phosphorylation confers selective toxicity. In conclusion, although we provide a mechanism distinct from that reported previously, the ability of DCA to target cell lines with defects in the electron transport chain and to synergize with existing chemotherapeutics supports further preclinical development.

The burden of cervical cancer in China has not been characterized in detail. We reviewed cervical cancer data from national mortality surveys and registries, and conducted a meta‐analysis to estimate the prevalence of high‐grade lesions (HSIL) and high‐risk human papillomavirus (HR‐HPV) infections in rural Shanxi Province. We found that a national survey in the 1970s estimated age‐standardized cervical cancer mortality rates as ∼15 and ∼83/100,000 women nationally and in Xiangyuan, Shanxi; but the latest survey (2004–2005) found much lower rates of ∼3 and ∼7/100,000, respectively. IARC registries record age‐standardized cervical cancer incidence in China as <5/100,000 (1998–2002); but the five registry sites cover <2% of the population, and the gross domestic product per capita at each of the registry sites is higher than China's average (by a factor ranging from 1.3 to 3.9). The pooled estimate of the prevalence of HSIL and HR‐HPV in women aged 30–54 years in Shanxi was 3.7%(95%CI:2.7–4.8%) and 17.2%(95%CI:13.1–21.3%), respectively. Based on a feasible range informed by the incidence data for China and other unscreened populations, the predicted indicative annual number of new cervical cancer cases nationally, in the absence of any intervention, ranges from ∼27,000 to 130,000 (2010) to 42,000 to 187,000 (2050). In conclusion, recent data suggest comparatively low rates of cervical cancer incidence in China, which may be partly explained by the location of registry sites in higher socioeconomic status areas. However, the evidence is consistent with considerable heterogeneity within China, with a higher disease burden in some rural areas such as Shanxi. Therefore, the lower reported rates of cervical cancer in China should be interpreted cautiously.

Non‐small cell lung cancer (NSCLC) is the leading cause of cancer death globally. To develop better diagnostics and more effective treatments, research in the past decades has focused on identification of molecular changes in the genome, transcriptome, proteome, and more recently also the metabolome. Phospholipids, which nevertheless play a central role in cell functioning, remain poorly explored. Here, using a mass spectrometry (MS)‐based phospholipidomics approach, we profiled 179 phospholipid species in malignant and matched non‐malignant lung tissue of 162 NSCLC patients (73 in a discovery cohort and 89 in a validation cohort). We identified 91 phospholipid species that were differentially expressed in cancer versus non‐malignant tissues. Most prominent changes included a decrease in sphingomyelins (SMs) and an increase in specific phosphatidylinositols (PIs). Also a decrease in multiple phosphatidylserines (PSs) was observed, along with an increase in several phosphatidylethanolamine (PE) and phosphatidylcholine (PC) species, particularly those with 40 or 42 carbon atoms in both fatty acyl chains together. 2D‐imaging MS of the most differentially expressed phospholipids confirmed their differential abundance in cancer cells. We identified lipid markers that can discriminate tumor versus normal tissue and different NSCLC subtypes with an AUC (area under the ROC curve) of 0.999 and 0.885, respectively. In conclusion, using both shotgun and 2D‐imaging lipidomics analysis, we uncovered a hitherto unrecognized alteration in phospholipid profiles in NSCLC. These changes may have important biological implications and may have significant potential for biomarker development.

The purpose of our study was to evaluate the frequency of hypermethylated tumor suppressor genes (TSGs) in peripheral blood, mouth and throat (M&T) rinsing fluid and nasopharyngeal (NP) swabs of nasopharyngeal carcinoma (NPC) patients. Six normal NP tissues, 43 M&T rinsing fluid, 37 NP swabs and 43 peripheral blood from healthy non‐smokers and non‐drinkers without a family history of NPC, and 30 NPC tumors and their matched body fluid were analyzed for the presence of hypermethylated p15, p16, Ras association domain family 1 (RASSF1A), E‐cadherin, and death‐associated protein kinase (DAPK) by methylation‐specific PCR. Sequencing analysis was carried out on selected NPC tumors and body fluid samples. Twenty‐nine (97%) tumors displayed methylation in at least 1 of the 5 genes. The methylation frequencies were 80% for p15, 77% for DAPK, 67% for RASSF1A, 53% for E‐cadherin and 33% for p16. The frequency range of aberrant methylated genes in the body fluids were NP swabs (17–63%) and M&T rinsing fluid (17–50%). Methylation was found in <20% of peripheral blood for each respective gene. Methylation was, however, detected in 1 M&T rinsing fluid in which the primary tumor showed methylation free for RASSF1A. Five healthy individuals exhibited methylation for DAPK, or RASSF1A, or p15 in their body fluid samples. All body fluid samples of healthy controls showed methylation free for E‐cadherin and p16. Epigenetic change is found frequently in NPC and the high detection rate in body fluids suggest its potential application in non‐invasive screening of NPC or detection of residual carcinoma after treatment. © 2003 Wiley‐Liss, Inc.

Proprotein convertases are proteases that have been implicated in the activation of a wide variety of proteins. These proteins are generally synthesised as precursor proteins and require limited proteolysis for conversion into their mature bioactive counterparts. Many of these proteins, including metalloproteases, growth factors and their receptors or adhesion molecules, have been shown to facilitate tumour formation and progression. Hence, this review will focus on the proprotein convertase furin and its role in cancer. The expression of furin has been confirmed in a large spectrum of cancers such as head and neck squamous cell carcinoma, breast cancer and rhabdomyosarcoma. Functional studies modulating furin activity uncovered its importance for the processing of many cancer‐related substrates and strongly indicate that high furin activity promotes the malignant phenotype of cancer cells. In this review, we summarise the expression and function of furin in different cancer types, discuss its role in processing cancer‐related proproteins and give examples of potential therapeutic approaches that take advantage of the proteolytic activity of furin in cancer cells.

Ferric nitrilotriacetate (Fe-NTA) gây hoại tử ống thận gần, hậu quả của tổn thương liên quan đến các ion sắt và gốc tự do, cuối cùng dẫn đến tỷ lệ cao mắc ung thư biểu mô tuyến thận ở chuột đực và chuột nhắt. Chúng tôi đã nghiên cứu các mức độ biến đổi base DNA điển hình gây ra bởi gốc hydroxyl trong nhiễm sắc thể thận của chuột Wistar đực được xử lý với một hoặc nhiều liệu trình Fe-NTA. Năm base DNA cải biến từ pyrimidine và 5 base cải biến từ purine đã được xác định và định lượng bằng sắc ký khí/phổ khối với theo dõi ion chọn lọc. Các base được cải biến bao gồm 5-hydroxy-5-methylhydantoin, 5-(hydroxymethyl)uracil, 5-hydroxy-cytosine, thymine glycol, 5,6-dihydoxyuraril, 4,6-diamino-5-form-amidopyrimidine, 8-hydroxyadenine, xanthine, 2-hydroxyadenine và 8-hydroxyguanine. Hàm lượng hầu hết các hợp chất này đã tăng đáng kể so với mức đối chứng trong nhiễm sắc thể thận của chuột được xử lý Fe-NTA như đã đo sau 3 và 24 giờ sau điều trị. Mức độ tăng cao của các base cải biên kèm theo với sự hoại tử của ống lượn gần. Tuy nhiên, vào ngày thứ 19, không quan sát thấy sự tích tụ của các base DNA cải biên. Về mặt hình thái, các tế bào karyomegaiic phân tán được thấy trong ống thận gần, nhưng hoại tử hiếm khi được tìm thấy. Một số tổn thương base DNA đã được xác định là gây đột biến, mặc dù một số khác chưa được điều tra. Sự hiện diện của các base DNA cải biên đồng thời với hoại tử và tái sinh của các ống lượn gần thận có thể là một bước quan trọng trong quá trình gây ung thư bởi Fe-NTA. © Wiley-Liss, Inc.