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246 KiB

Open AccessArticle

Genetic Variants in Human Leukocyte Antigen-DP Influence Both Hepatitis C Virus Persistence and Hepatitis C Virus F Protein Generation in the Chinese Han Population

by Xiaodong Xu, Ming Yue, Longfeng Jiang, Xiaozhao Deng, Yongxiang Zhang, Yun Zhang, Danyan Zhu, Wen Xiao, Zhenxian Zhou, Wenjuan Yao, Jing Kong, Xiaojie Yu and Juan Wei

Int. J. Mol. Sci. 2014, 15(6), 9826-9843; https://doi.org/10.3390/ijms15069826 - 3 Jun 2014

Cited by 10 | Viewed by 7459

Abstract

Chronic hepatitis C is a serious liver disease that often results in cirrhosis or hepatocellular carcinoma. The aim of this study was to assess the association of human leukocyte antigen-DP (HLA-DP) variants with risk of chronic hepatitis C virus (HCV) [...] Read more.

Chronic hepatitis C is a serious liver disease that often results in cirrhosis or hepatocellular carcinoma. The aim of this study was to assess the association of human leukocyte antigen-DP (HLA-DP) variants with risk of chronic hepatitis C virus (HCV) or anti-F antibody generation. We selected two single nucleotide polymorphisms (SNPs) in a region including HLA-DPA1 (rs3077) and HLA-DPB1 (rs9277534) and genotyped SNPs in 702 cases and 342 healthy controls from the Chinese population using TaqMan SNP genotyping assay. Moreover, the exon 2 of the HLA-DPA1 and HLA-DPB1 genes were amplified and determined by sequencing-based typing (SBT). The results showed that rs3077 significantly increased the risk of chronic HCV infection in additive models and dominant models (odds ratio (OR) = 1.32 and 1.53). The rs3077 also contributed to decrease the risk of anti-F antibody generation in additive models and dominant models (OR = 0.46 and 0.56). Subsequent analyses revealed the risk haplotypes (DPA1*0103-DPB1*0501 and DPA1*0103-DPB1*0201) and protective haplotypes (DPA1*0202-DPB1*0501 and DPA1*0202-DPB1*0202) to chronic HCV infection. Moreover, we also found that the haplotype of DPA1*0103-DPB1*0201 and DPA1*0202-DPB1*0202 were associated with the anti-F antibody generation. Our findings show that genetic variants in HLA-DP gene are associated with chronic HCV infection and anti-F antibody generation. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Nipple Discharge of CA15-3, CA125, CEA and TSGF as a New Biomarker Panel for Breast Cancer

by Gangping Wang, Yan Qin, Junxi Zhang, Jinhui Zhao, Yun'ai Liang, Zuofeng Zhang, Meihua Qin and Yanqing Sun

Int. J. Mol. Sci. 2014, 15(6), 9546-9565; https://doi.org/10.3390/ijms15069546 - 28 May 2014

Cited by 58 | Viewed by 9529

Abstract

Breast cancer is the second leading cause of cancer death in women. Serum biomarkers such as cancer antigen 15-3 (CA15-3), cancer antigen 125 (CA125), and carcinoembryonic antigen (CEA) can be used as diagnostic and prognostic factors and can also provide valuable information during [...] Read more.

Breast cancer is the second leading cause of cancer death in women. Serum biomarkers such as cancer antigen 15-3 (CA15-3), cancer antigen 125 (CA125), and carcinoembryonic antigen (CEA) can be used as diagnostic and prognostic factors and can also provide valuable information during follow-up. However, serum protein biomarkers show limited diagnostic sensitivity and specificity in stand-alone assays because their levels reflect tumor burden. To validate whether biomarkers in nipple discharge may serve as novel biomarkers for breast cancer, we composed a panel of potential cancer biomarkers, including CA15-3, CA125, CEA, and malignant tumor-specific growth factor (TSGF), and evaluated their expression in both serum and nipple discharge in order to explore the expression and significance of estrogen receptor (ER), progestrone receptor (PR), epidermal growth factor receptor type 2 (HER2/neu), CA15-3, CA125, CEA, and TSGF expression for their combined predictive value for breast cancer and in judging the prognosis of breast cancer. Univariate analysis revealed that combined detection of CA15-3, CA125, CEA, and TSGF in nipple discharge served as novel biomarkers for the diagnosis and prognosis of breast cancer, but in the multivariate analyses the adverse effects of the four biomarkers combination in nipple discharge positivity on overall survival were lost. Multivariate analysis revealed that the positivity of the combined detection of the four biomarkers in both nipple discharge and serum was significantly higher than that of other detection methods. Thus, the combined detection of these four biomarkers both in serum and nipple discharge was retained as an independent prognostic variable in breast cancer patients. Our results indicate that CA15-3, CA125, CEA, and TSGF in nipple discharge can serve as novel biomarkers in the diagnosis and prognosis of breast cancer. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Silencing of Ether à Go-Go 1 by shRNA Inhibits Osteosarcoma Growth and Cell Cycle Progression

by Jin Wu, Daixing Zhong, Xijin Fu, Qingjun Liu, Liangqi Kang and Zhenqi Ding

Int. J. Mol. Sci. 2014, 15(4), 5570-5581; https://doi.org/10.3390/ijms15045570 - 1 Apr 2014

Cited by 21 | Viewed by 6695

Abstract

Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the [...] Read more.

Recently, a member of the voltage-dependent potassium channel (Kv) family, the Ether à go-go 1 (Eag1) channel was found to be necessary for cell proliferation, cycle progression and tumorigenesis. However, the therapeutic potential of the Eag1 channel in osteosarcoma remains elusive. In the present study, a recombinant adenovirus harboring shRNA against Eag1 was constructed to silence Eag1 expression in human osteosarcoma MG-63 cells. We observed that Eag1-shRNA inhibited the proliferation and colony formation of MG-63 cells due to the induction of G1 phase arrest. Moreover, in vivo experiments showed that Eag1-shRNA inhibited osteosarcoma growth in a xenograft nude mice model. In addition, selective inhibition of Eag1 significantly decreased the expression levels of cyclin D1 and E. Taken together, our data suggest that the Eag1 channel plays a crucial role in regulating the proliferation and cell cycle of osteosarcoma cells, and represents a new and effective therapeutic target for osteosarcoma. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Role of VEGF-A and Its Receptors in Sporadic and MEN2-Associated Pheochromocytoma

by Carla Vaz Ferreira, Débora Rodrigues Siqueira, Mírian Romitti, Lucieli Ceolin, Beatriz Assis Brasil, Luise Meurer, Clarissa Capp and Ana Luiza Maia

Int. J. Mol. Sci. 2014, 15(4), 5323-5336; https://doi.org/10.3390/ijms15045323 - 26 Mar 2014

Cited by 9 | Viewed by 6892

Abstract

Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. [...] Read more.

Pheochromocytoma (PHEO), a rare catecholamine producing tumor arising from the chromaffin cells, may occurs sporadically (76%–80%) or as part of inherited syndromes (20%–24%). Angiogenesis is a fundamental step in tumor proliferation and vascular endothelial growth factor (VEGF-A) is the most well-characterized angiogenic factor. The role of angiogenic markers in PHEO is not fully understood; investigations were therefore made to evaluate the expression of VEGF-A and its receptors in PHEO and correlate to clinical parameters. Twenty-nine samples of PHEO were evaluated for VEGF-A, VEGF receptor-1 (VEGFR-1) VEGFR-2 expression and microvessel density (MVD) by immunohistochemistry. Clinical data were reviewed in medical records. The mean age of patients was 38 ± 14 years, and 69% were woman. VEGF-A, VEGFR-1 and VEGFR-2 staining were detected in nearly all PHEO samples. No significant correlation was observed between VEGF-A, VEGFR-1, VEGFR-2 expression or MVD and age at diagnosis, tumor size or sporadic and hereditary PHEO. However, the levels of expression of these molecules were significantly higher in malignant PHEO samples (p = 0.027, p = 0.003 and p = 0.026, respectively).VEGF-A and its receptors were shown to be up-regulated in malignant PHEO, suggesting that these molecules might be considered as therapeutic targets for unresectable or metastatic tumors. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Activation of VCAM-1 and Its Associated Molecule CD44 Leads to Increased Malignant Potential of Breast Cancer Cells

by Pei-Chen Wang, Ching-Chieh Weng, You-Syuan Hou, Shu-Fang Jian, Kuan-Te Fang, Ming-Feng Hou and Kuang-Hung Cheng

Int. J. Mol. Sci. 2014, 15(3), 3560-3579; https://doi.org/10.3390/ijms15033560 - 27 Feb 2014

Cited by 43 | Viewed by 9189

Abstract

VCAM-1 (CD106), a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In the present study, we observed that VCAM-1 expression can be induced in many breast [...] Read more.

VCAM-1 (CD106), a transmembrane glycoprotein, was first reported to play an important role in leukocyte adhesion, leukocyte transendothelial migration and cell activation by binding to integrin VLA-1 (α4β1). In the present study, we observed that VCAM-1 expression can be induced in many breast cancer epithelial cells by cytokine stimulation in vitro and its up-regulation directly correlated with advanced clinical breast cancer stage. We found that VCAM-1 over-expression in the NMuMG breast epithelial cells controls the epithelial and mesenchymal transition (EMT) program to increase cell motility rates and promote chemoresistance to doxorubicin and cisplatin in vitro. Conversely, in the established MDAMB231 metastatic breast cancer cell line, we confirmed that knockdown of endogenous VCAM-1 expression reduced cell proliferation and inhibited TGFβ1 or IL-6 mediated cell migration, and increased chemosensitivity. Furthermore, we demonstrated that knockdown of endogenous VCAM-1 expression in MDAMB231 cells reduced tumor formation in a SCID xenograft mouse model. Signaling studies showed that VCAM-1 physically associates with CD44 and enhances CD44 and ABCG2 expression. Our findings uncover the possible mechanism of VCAM-1 activation facilitating breast cancer progression, and suggest that targeting VCAM-1 is an attractive strategy for therapeutic intervention. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Risk-Association of Five SNPs in TOX3/LOC643714 with Breast Cancer in Southern China

by Xuanqiu He, Guangyu Yao, Fenxia Li, Ming Li and Xuexi Yang

Int. J. Mol. Sci. 2014, 15(2), 2130-2141; https://doi.org/10.3390/ijms15022130 - 29 Jan 2014

Cited by 24 | Viewed by 7506

Abstract

The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may [...] Read more.

The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612); Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 ((95% confidence intervals (CI), 1.10–1.57)) and 1.26 (95% CI, 1.02–1.56), respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

The Antidiabetic Drug Metformin Inhibits the Proliferation of Bladder Cancer Cells in Vitro and in Vivo

by Tao Zhang, Peng Guo, Yinan Zhang, Hui Xiong, Xiao Yu, Shan Xu, Xinyang Wang, Dalin He and Xunbo Jin

Int. J. Mol. Sci. 2013, 14(12), 24603-24618; https://doi.org/10.3390/ijms141224603 - 18 Dec 2013

Cited by 71 | Viewed by 9728

Abstract

Recent studies suggest that metformin, a widely used antidiabetic agent, may reduce cancer risk and improve prognosis of certain malignancies. However, the mechanisms for the anti-cancer effects of metformin remain uncertain. In this study, we investigated the effects of metformin on human bladder [...] Read more.

Recent studies suggest that metformin, a widely used antidiabetic agent, may reduce cancer risk and improve prognosis of certain malignancies. However, the mechanisms for the anti-cancer effects of metformin remain uncertain. In this study, we investigated the effects of metformin on human bladder cancer cells and the underlying mechanisms. Metformin significantly inhibited the proliferation and colony formation of 5637 and T24 cells in vitro; specifically, metformin induced an apparent cell cycle arrest in G0/G1 phases, accompanied by a strong decrease of cyclin D1, cyclin-dependent kinase 4 (CDK4), E2F1 and an increase of p21^waf^-¹. Further experiments revealed that metformin activated AMP-activated protein kinase (AMPK) and suppressed mammalian target of rapamycin (mTOR), the central regulator of protein synthesis and cell growth. Moreover, daily treatment of metformin led to a substantial inhibition of tumor growth in a xenograft model with concomitant decrease in the expression of proliferating cell nuclear antigen (PCNA), cyclin D1 and p-mTOR. The in vitro and in vivo results demonstrate that metformin efficiently suppresses the proliferation of bladder cancer cells and suggest that metformin may be a potential therapeutic agent for the treatment of bladder cancer. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Radiation-Sensitising Effects of Antennapedia Proteins (ANTP)-SmacN7 on Tumour Cells

by Li Qing Du, Yan Wang, Chang Xu, Jia Cao, Qin Wang, Hui Zhao, Fei Yue Fan, Bing Wang, Takanori Katsube, Sai Jun Fan and Qiang Liu

Int. J. Mol. Sci. 2013, 14(12), 24087-24096; https://doi.org/10.3390/ijms141224087 - 11 Dec 2013

Cited by 9 | Viewed by 6141

Abstract

The objective of this study was to investigate the underlying mechanisms behind the radiation-sensitising effects of the antennapedia proteins (ANTP)-smacN7 fusion protein on tumour cells. ANTP-SmacN7 fusion proteins were synthesised, and the ability of this fusion protein to penetrate cells was observed. Effects [...] Read more.

The objective of this study was to investigate the underlying mechanisms behind the radiation-sensitising effects of the antennapedia proteins (ANTP)-smacN7 fusion protein on tumour cells. ANTP-SmacN7 fusion proteins were synthesised, and the ability of this fusion protein to penetrate cells was observed. Effects of radiation on the expression of X-linked inhibitor of apoptosis protein (XIAP) were detected by western blotting. The radiation-sensitising effects of ANTP-SmacN7 fusion proteins were observed by a clonogenic assay. The effects of drugs and radiation on tumour cell apoptosis were determined using Annexin V/FITC double staining. Changes in caspase-8, caspase-9 and caspase-3 were detected by western blot before and after ANTP-SmacN7 inhibition of XIAP. The ANTP-SmacN7 fusion protein could enter and accumulate in cells; in vitro XIAP expression of radiation-induced tumour cells was negatively correlated with tumour radiosensitivity. The ANTP-SmacN7 fusion protein promoted tumour cell apoptosis through the activation of caspase3. ANTP-SmacN7 fusion protein may reduce tumour cell radioresistance by inducing caspase3 activation. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Prognostic Discrimination Using a 70-Gene Signature among Patients with Estrogen Receptor-Positive Breast Cancer and an Intermediate 21-Gene Recurrence Score

by Sung Gwe Ahn, Hak Min Lee, Hak Woo Lee, Seung Ah Lee, Se-Ra Lee, Sun-Hee Leem, Joon Jeong and In-Sun Chu

Int. J. Mol. Sci. 2013, 14(12), 23685-23699; https://doi.org/10.3390/ijms141223685 - 4 Dec 2013

Cited by 13 | Viewed by 6493

Abstract

The Oncotype DX^® recurrence score (RS) predictor has been clinically utilized to appropriately select adjuvant chemotherapy for patients with estrogen receptor (ER)-positive early breast cancer. However, the selection of chemotherapy for patients with intermediate RSs remains controversial. We assessed the prognostic value [...] Read more.

The Oncotype DX^® recurrence score (RS) predictor has been clinically utilized to appropriately select adjuvant chemotherapy for patients with estrogen receptor (ER)-positive early breast cancer. However, the selection of chemotherapy for patients with intermediate RSs remains controversial. We assessed the prognostic value of a 70-gene signature (70GS) among patients with ER-positive breast cancer and intermediate RSs. In addition, we sought to identify genes associated with poor 70GS scores based on gene expression profiling (GEP). GEP was performed using gene expression data from 186 patients with ER-positive breast cancer. The RS and 70GS score were calculated on the basis of GEP. Among 186 patients, 82 ER-positive patients with intermediate RSs were identified. These patients were stratified by 70GS, overall survival (OS) significantly differed according to 70GS (p = 0.013). In a supervised hierarchical analysis according to 70GS, the expression of several representative genes for cell proliferation was significantly higher in the poor 70GS cluster than in the good 70GS cluster. Furthermore, among these patients, FOXM1, AURKA, AURKB, and BIRC5 displayed prognostic significance for OS. In conclusion, 70GS can help to discriminate survival differences among ER-positive patients with intermediate RSs. FOXM1, AURKA, AURKB, and BIRC5, are associated with poor 70GS scores. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Aberrant Expression of Posterior HOX Genes in Well Differentiated Histotypes of Thyroid Cancers

by Monica Cantile, Giosuè Scognamiglio, Lucia La Sala, Elvira La Mantia, Veronica Scaramuzza, Elena Valentino, Fabiana Tatangelo, Simona Losito, Luciano Pezzullo, Maria Grazia Chiofalo, Franco Fulciniti, Renato Franco and Gerardo Botti

Int. J. Mol. Sci. 2013, 14(11), 21727-21740; https://doi.org/10.3390/ijms141121727 - 1 Nov 2013

Cited by 39 | Viewed by 7539

Abstract

Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, [...] Read more.

Molecular etiology of thyroid cancers has been widely studied, and several molecular alterations have been identified mainly associated with follicular and papillary histotypes. However, the molecular bases of the complex pathogenesis of thyroid carcinomas remain poorly understood. HOX genes regulate normal embryonic development, cell differentiation and other critical processes in eukaryotic cell life. Several studies have shown that HOX genes play a role in neoplastic transformation of several human tissues. In particular, the genes belonging to HOX paralogous group 13 seem to hold a relevant role in both tumor development and progression. We have identified a significant prognostic role of HOX D13 in pancreatic cancer and we have recently showed the strong and progressive over-expression of HOX C13 in melanoma metastases and deregulation of HOX B13 expression in bladder cancers. In this study we have investigated, by immunohistochemisty and quantitative Real Time PCR, the HOX paralogous group 13 genes/proteins expression in thyroid cancer evolution and progression, also evaluating its ability to discriminate between main histotypes. Our results showed an aberrant expression, both at gene and protein level, of all members belonging to paralogous group 13 (HOX A13, HOX B13, HOX C13 and HOX D13) in adenoma, papillary and follicular thyroid cancers samples. The data suggest a potential role of HOX paralogous group 13 genes in pathogenesis and differential diagnosis of thyroid cancers. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Probing Antigen-Antibody Interaction Using Fluorescence Coupled Capillary Electrophoresis

by Jianhao Wang, Lin Qiu, Cheli Wang, Yue Zhang, Jingyan Li, Jiang Xia and Pengju Jiang

Int. J. Mol. Sci. 2013, 14(9), 19146-19154; https://doi.org/10.3390/ijms140919146 - 17 Sep 2013

Cited by 11 | Viewed by 7457

Abstract

In this report, the use of fluorescence detection coupled capillary electrophoresis (CE-FL) allowed us to fully characterize the antigen-antibody interaction. CE-FL allowed separation of unbound quantum dots (QDs) and ligand bound QDs and also revealed an ordered assembly of biomolecules on QDs. Further, [...] Read more.

In this report, the use of fluorescence detection coupled capillary electrophoresis (CE-FL) allowed us to fully characterize the antigen-antibody interaction. CE-FL allowed separation of unbound quantum dots (QDs) and ligand bound QDs and also revealed an ordered assembly of biomolecules on QDs. Further, we observed FRET from QDs donor to DyLight acceptor, which were covalently conjugated with human IgG and goat anti-human IgG, respectively. The immunocomplex was formed and the mutual affinity of the antigen and antibody brought QDs and DyLight close enough to allow FRET to occur. This novel CE-based technique can be easily extended to other FRET systems based on QDs and may have potential application in the detection of antibodies. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Inhibition of Stromal PlGF Suppresses the Growth of Prostate Cancer Xenografts

by Karin Zins, Anita Thomas, Trevor Lucas, Mouldy Sioud, Seyedhossein Aharinejad and Dietmar Abraham

Int. J. Mol. Sci. 2013, 14(9), 17958-17971; https://doi.org/10.3390/ijms140917958 - 3 Sep 2013

Cited by 13 | Viewed by 7112

Abstract

The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF). PlGF is a member of the [...] Read more.

The growth and vascularization of prostate cancer is dependent on interactions between cancer cells and supporting stromal cells. The primary stromal cell type found in prostate tumors is the carcinoma-associated fibroblast, which produces placental growth factor (PlGF). PlGF is a member of the vascular endothelial growth factor (VEGF) family of angiogenic molecules and PlGF mRNA levels increase after androgen deprivation therapy in prostate cancer. In this study, we show that PlGF has a direct dose-dependent proliferative effect on human PC-3 prostate cancer cells in vitro and fibroblast-derived PlGF increases PC-3 proliferation in co-culture. In xenograft tumor models, intratumoral administration of murine PlGF siRNA reduced stromal-derived PlGF expression, reduced tumor burden and decreased the number of Ki-67 positive proliferating cells associated with reduced vascular density. These data show that targeting stromal PlGF expression may represent a therapeutic target for the treatment of prostate cancer. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

Low Amount of Salinomycin Greatly Increases Akt Activation, but Reduces Activated p70S6K Levels

by Ju-Hwa Kim, Ae-Ran Choi, Yong Kee Kim, Hyung Sik Kim and Sungpil Yoon

Int. J. Mol. Sci. 2013, 14(9), 17304-17318; https://doi.org/10.3390/ijms140917304 - 22 Aug 2013

Cited by 18 | Viewed by 7509

Abstract

The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules [...] Read more.

The present study identified a novel salinomycin (Sal)-sensitization mechanism in cancer cells. We analyzed the signal proteins Akt, Jnk, p38, Jak, and Erk1/2 in cancer cell lines that had arrested growth following low amounts of Sal treatment. We also tested the signal molecules PI3K, PDK1, GSK3β, p70S6K, mTOR, and PTEN to analyze the PI3K/Akt/mTOR pathway. The results showed that Sal sensitization positively correlates with large reductions in p70S6K activation. Interestingly, Akt was the only signal protein to be significantly activated by Sal treatment. The Akt activation appeared to require the PI3K pathway as its activation was abolished by the PI3K inhibitors LY294002 and wortmannin. The Akt activation by Sal was conserved in the other cell lines analyzed, which originated from other organs. Both Akt activation and C-PARP production were proportionally increased with increased doses of Sal. In addition, the increased levels of pAkt were not reduced over the time course of the experiment. Co-treatment with Akt inhibitors sensitized the Sal-treated cancer cells. The results thereby suggest that Akt activation is increased in cells that survive Sal treatment and resist the cytotoxic effect of Sal. Taken together; these results indicate that Akt activation may promote the resistance of cancer cells to Sal. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Resveratrol Sensitizes Tamoxifen in Antiestrogen-Resistant Breast Cancer Cells with Epithelial-Mesenchymal Transition Features

by Xiao-Peng Shi, Shan Miao, Yin Wu, Wei Zhang, Xiao-Fang Zhang, Hua-Zhao Ma, Hai-Li Xin, Juan Feng, Ai-Dong Wen and Yan Li

Int. J. Mol. Sci. 2013, 14(8), 15655-15668; https://doi.org/10.3390/ijms140815655 - 26 Jul 2013

Cited by 69 | Viewed by 11771

Abstract

Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a [...] Read more.

Tamoxifen resistance remains to be a huge obstacle in the treatment of hormone-dependent breast cancer, and this therefore highlights the dire need to explore the underlying mechanisms. The epithelial-mesenchymal transition (EMT) is a molecular process through which an epithelial cell transfers into a mesenchymal phenotype. Roles of EMT in embryo development, cancer invasion and metastasis have been extensively reported. Herein, we established tamoxifen-resistant MCF-7/TR breast cancer cells and showed that MCF-7/TR cells underwent EMT driven by enhanced endogenous TGF-β/Smad signaling. Ectopic supplement of TGF-β promoted in MCF-7 cells a mesenchymal and resistant phenotype. In parallel, we demonstrated that resveratrol was capable of synergizing with tamoxifen and triggering apoptosis in MCF-7/TR cells. Further Western blot analysis indicated that the chemosensitizing effects of resveratrol were conferred with its modulation on endogenous TGF-β production and Smad phosphorylation. In particular, 50 μM resveratrol had minor effects on MCF-7/TR cell proliferation, but could significantly attenuate endogenous TGF-β production and the Smad pathway, ultimately leading to reversion of EMT. Collectively, our study highlighted distinct roles of EMT in tamoxifen resistance and resveratrol as a potential agent to overcome acquired tamoxifen resistance. The molecular mechanism of resveratrol chemosensitizing effects is, at least in part, TGF-β/Smad-dependent. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Open AccessArticle

TMPRSS4 as a Poor Prognostic Factor for Triple-Negative Breast Cancer

by Daye Cheng, Hong Kong and Yunhui Li

Int. J. Mol. Sci. 2013, 14(7), 14659-14668; https://doi.org/10.3390/ijms140714659 - 12 Jul 2013

Cited by 24 | Viewed by 6753

Abstract

Triple-negative breast cancer (TNBC) is characterized by the lack of immunohistochemical staining for estrogen receptors (ER), progesterone receptors (PR), and lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). Our aim was to investigate the expression of transmembrane protease, [...] Read more.

Triple-negative breast cancer (TNBC) is characterized by the lack of immunohistochemical staining for estrogen receptors (ER), progesterone receptors (PR), and lack of overexpression or amplification of human epidermal growth factor receptor 2 (HER2). Our aim was to investigate the expression of transmembrane protease, serine 4 (TMPRSS4) in TNBC patients and its possible relationship to the outcome of the disease. A total of 72 TNBC patients and 109 non-TNBC patients who were diagnosed between 2003 and 2008 were enrolled in this study. Immunohistochemistry was used to compare the expression pattern of TMPRSS4 in TNBC and non-TNBC groups, and the prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression in TNBC patients. The rate of high expression of TMPRSS4 was significantly higher in TNBC group than that in non-TNBC group. High expression of TMPRSS4 was significantly correlated with lymph node metastasis, histological grade, and tumor size. TNBC patients with high TMPRSS4 expression showed the poorer overall survival (OS) and disease-free survival (DFS) than those patients with low TMPRSS4 expression. In multivariate analysis, only lymph node metastasis and TMPRSS4 expression were the independent prognostic factors for OS and DFS in TNBC. Our study provides evidence that TMPRSS4 expression is associated with lymph node metastasis, tumor size, and histological grade in TNBC patients, and also is an independent prognostic factor for TNBC. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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p38β, A Novel Regulatory Target of Pokemon in Hepatic Cells

by Zhe Chen, Feng Liu, Nannan Zhang, Deliang Cao, Min Liu, Ying Tan and Yuyang Jiang

Int. J. Mol. Sci. 2013, 14(7), 13511-13524; https://doi.org/10.3390/ijms140713511 - 27 Jun 2013

Cited by 10 | Viewed by 7502

Abstract

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular [...] Read more.

Pokemon is an important proto-oncogene involved in various biological processes and cancer development, such as cell differentiation, tumorigenesis and metastasis. Pokemon is recognized as a transcription factor localized upstream of several oncogenes, regulating their expression. p38MAPKs act as key regulatory factors in cellular signaling pathways associated with inflammatory responses, cell proliferation, differentiation and survival. p38β, a member of p38MAPK family, is closely correlated with tumorigenesis, but the mechanism of activation remains unclear. In this study, we found overexpression of Pokemon promoted the growth, migration and invasion of HepG2 cells. However, a p38 inhibitor SB202190 efficiently attenuated the promoting effect of Pokemon in the HepG2 cells. Targeted expression or silencing of Pokemon changed cellular p38β protein level and phosphorylation of downstream ATF2 in the p38 signaling pathway. Both dual luciferase report assay and ChIP assay suggested that p38β is a novel regulatory target of the transcription factor Pokemon and positively regulated by Pokemon in hepatic cells. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Combination of Low Concentration of (−)-Epigallocatechin Gallate (EGCG) and Curcumin Strongly Suppresses the Growth of Non-Small Cell Lung Cancer in Vitro and in Vivo through Causing Cell Cycle Arrest

by Dong-Hu Zhou, Xuemin Wang, Mingmin Yang, Xiaoyan Shi, Wenbin Huang and Qing Feng

Int. J. Mol. Sci. 2013, 14(6), 12023-12036; https://doi.org/10.3390/ijms140612023 - 5 Jun 2013

Cited by 82 | Viewed by 11037

Abstract

(−)-Epigallocatechin gallate (EGCG) and curcumin are two naturally derived agents that have been widely investigated worldwide. They exhibit their anti-tumor effects in many types of cancers. In the current study, the effect of the combination of the two agents on non-small cell lung [...] Read more.

(−)-Epigallocatechin gallate (EGCG) and curcumin are two naturally derived agents that have been widely investigated worldwide. They exhibit their anti-tumor effects in many types of cancers. In the current study, the effect of the combination of the two agents on non-small cell lung cancer (NSCLC) cells was investigated. The results revealed that at low concentrations, the combination of the EGCG and curcumin strongly enhanced cell cycle arrest. Flow cytometry analysis showed that the cells were arrested at G1 and S/G2 phases. Two main cell cycle related proteins cyclin D1 and cyclin B1 were significantly inhibited at the present of EGCG and curcumin. EdU (5-ethynyl-2'-deoxyuridine) fluorescence staining showed that the DNA replication was significantly blocked. A clonal growth assay also confirmed a marked repression of cell growth. In a lung cancer xenograft node mice model, combination of EGCG and curcumin exhibited protective effect against weight loss due to tumor burden. Tumor growth was strongly repressed by the combination of the two agents, without causing any serious side-effect. Overall, these results strongly suggest that EGCG in combination with curcumin could be a candidate for chemoprevention agent of NSCLC. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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RANK/RANK-L/OPG in Patients with Bone Metastases Treated with Anticancer Agents and Zoledronic Acid: A Prospective Study

by Laura Mercatali, Marianna Ricci, Emanuela Scarpi, Patrizia Serra, Francesca Fabbri, Rossana Ricci, Chiara Liverani, Michele Zanoni, Wainer Zoli, Roberta Maltoni, Erica Gunelli, Dino Amadori and Toni Ibrahim

Int. J. Mol. Sci. 2013, 14(6), 10683-10693; https://doi.org/10.3390/ijms140610683 - 23 May 2013

Cited by 16 | Viewed by 7782

Abstract

Patients with solid cancer frequently develop bone metastases (BM). Zoledronic acid (Zometa^®, ZA), routinely used to treat patients with BM, acts on osteoclasts and also has antitumor properties. We aimed to assess the effect of ZA over time in novel bone [...] Read more.

Patients with solid cancer frequently develop bone metastases (BM). Zoledronic acid (Zometa^®, ZA), routinely used to treat patients with BM, acts on osteoclasts and also has antitumor properties. We aimed to assess the effect of ZA over time in novel bone turnover markers (RANK/receptor activator of nuclear factor-k B ligand (RANK-L)/ Osteoprotegerin (OPG)) and to correlate these with serum N-terminal telopeptide (NTX). The study prospectively evaluated levels of RANK, RANK-L and OPG transcripts by real-time PCR and NTX expression by ELISA in the peripheral blood of 49 consecutive patients with advanced breast, lung or prostate cancer. All patients received the standard ZA schedule and were monitored for 12 months. Median baseline values of RANK, RANK-L and OPG were 78.28 (range 7.34–620.64), 319.06 (21.42–1884.41) and 1.52 (0.10–58.02), respectively. At 12 months, the median RANK-L value had decreased by 22% with respect to the baseline, whereas median OPG levels had increased by about 96%. Consequently, the RANK-L/OPG ratio decreased by 56% from the baseline. Median serum NTX levels decreased over the 12-month period, reaching statistical significance (p < 0.0001). Our results would seem to indicate that ZA modulates RANK, RANK-L and OPG expression, thus decreasing osteoclast activity. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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An Exonuclease III Protection-Based Electrochemical Method for Estrogen Receptor Assay

by Sha Zhu, Ya Cao, Yuanyuan Xu, Yongmei Yin and Genxi Li

Int. J. Mol. Sci. 2013, 14(5), 10298-10306; https://doi.org/10.3390/ijms140510298 - 16 May 2013

Cited by 13 | Viewed by 7447

Abstract

Estrogen receptor (ER), expressed in approximately 80% of primary breast cancer cells, has proven to be a valuable predictive factor of the disease. Herein, by making use of the specific binding of ER to its DNA response elements, we propose an Exonuclease III [...] Read more.

Estrogen receptor (ER), expressed in approximately 80% of primary breast cancer cells, has proven to be a valuable predictive factor of the disease. Herein, by making use of the specific binding of ER to its DNA response elements, we propose an Exonuclease III (Exo III) protection-based electrochemical method for detecting ER proteins. In this assay, the presence of ER can protect the duplex DNA molecules immobilized on an electrode surface from Exo III-catalyzed digestion, resulting in an increased electrochemical signal. Experimental results have revealed that the proposed method can allow the quantification of ER in the range of 0.5 to 100 nM with a satisfactory detection limit of 0.38 nM. Furthermore, since this approach can also be employed to detect ER directly in nuclear extracts, it may be of great use in biomedical applications in the future. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Molecular Basis of Cardiac Myxomas

by Pooja Singhal, Adriana Luk, Vivek Rao and Jagdish Butany

Int. J. Mol. Sci. 2014, 15(1), 1315-1337; https://doi.org/10.3390/ijms15011315 - 20 Jan 2014

Cited by 38 | Viewed by 8744

Abstract

Cardiac tumors are rare, and of these, primary cardiac tumors are even rarer. Metastatic cardiac tumors are about 100 times more common than the primary tumors. About 90% of primary cardiac tumors are benign, and of these the most common are cardiac myxomas. [...] Read more.

Cardiac tumors are rare, and of these, primary cardiac tumors are even rarer. Metastatic cardiac tumors are about 100 times more common than the primary tumors. About 90% of primary cardiac tumors are benign, and of these the most common are cardiac myxomas. Approximately 12% of primary cardiac tumors are completely asymptomatic while others present with one or more signs and symptoms of the classical triad of hemodynamic changes due to intracardiac obstruction, embolism and nonspecific constitutional symptoms. Echocardiography is highly sensitive and specific in detecting cardiac tumors. Other helpful investigations are chest X-rays, magnetic resonance imaging and computerized tomography scan. Surgical excision is the treatment of choice for primary cardiac tumors and is usually associated with a good prognosis. This review article will focus on the general features of benign cardiac tumors with an emphasis on cardiac myxomas and their molecular basis. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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MicroRNAs and Triple Negative Breast Cancer

by Elvira D'Ippolito and Marilena V. Iorio

Int. J. Mol. Sci. 2013, 14(11), 22202-22220; https://doi.org/10.3390/ijms141122202 - 11 Nov 2013

Cited by 69 | Viewed by 8458

Abstract

Triple Negative Breast Cancer (TNBC) is a very aggressive tumor subtype, which still lacks specific markers for an effective targeted therapy. Despite the common feature of negativity for the three most relevant receptors (ER, PgR and HER2), TNBC is a very heterogeneous disease [...] Read more.

Triple Negative Breast Cancer (TNBC) is a very aggressive tumor subtype, which still lacks specific markers for an effective targeted therapy. Despite the common feature of negativity for the three most relevant receptors (ER, PgR and HER2), TNBC is a very heterogeneous disease where different subgroups can be recognized, and both gene and microRNA profiling studies have recently been carried out to dissect the different molecular entities. Moreover, several microRNAs playing a crucial role in triple negative breast cancer biology have been identified, providing the experimental basis for a possible therapeutic application. Indeed, the causal involvement of microRNAs in breast cancer and the possible use of these small noncoding RNA molecules as biomarkers has been extensively studied with promising results. Their application as therapeutic tools might represent an innovative approach, especially for a tumor subgroup still lacking an efficient and specific therapy such as TNBC. In this review, we summarize our knowledge on the most important microRNAs described in TNBC. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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MicroRNA-Regulated Pathways in Hematological Malignancies: How to Avoid Cells Playing Out of Tune

by Alessandro Fatica and Francesco Fazi

Int. J. Mol. Sci. 2013, 14(10), 20930-20953; https://doi.org/10.3390/ijms141020930 - 18 Oct 2013

Cited by 22 | Viewed by 7713

Abstract

The coordinated expression and interplay among lineage specific transcription factors and microRNAs contribute to the regulation of gene expression and determination of cell specificity. In hematopoietic stem cells (HSCs), unique combinations of transcription factors largely control growth and maturation of different blood cell [...] Read more.

The coordinated expression and interplay among lineage specific transcription factors and microRNAs contribute to the regulation of gene expression and determination of cell specificity. In hematopoietic stem cells (HSCs), unique combinations of transcription factors largely control growth and maturation of different blood cell lineages through cooperative regulation of specific target genes. MicroRNAs provide an additional level of control beyond transcription factors. By acting as regulators of crucial lineage-specific genetic programs, microRNAs direct early multipotential progenitor cells to adopt a certain cell fate program. Thus, alteration of specific microRNA levels may affect proliferation, differentiation and genetic stability of HSCs, contributing to the onset of myeloproliferative disorders and leukemia. The major aim of this review is to highlight the critical role of microRNA-regulated pathways during the establishment and progression of hematological malignancies, with a particular attention to leukemia, lymphomas and myelodysplastic syndromes. This will give us the opportunity to discuss the potential use of microRNA-based therapeutic approaches in these diseases. MicroRNAs are indeed emerging as relevant tools to improve the efficacy of currently used therapeutic protocols. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Carcinogenesis of Pancreatic Adenocarcinoma: Precursor Lesions

by Antonio Gnoni, Antonella Licchetta, Aldo Scarpa, Amalia Azzariti, Anna Elisabetta Brunetti, Gianni Simone, Patrizia Nardulli, Daniele Santini, Michele Aieta, Sabina Delcuratolo and Nicola Silvestris

Int. J. Mol. Sci. 2013, 14(10), 19731-19762; https://doi.org/10.3390/ijms141019731 - 30 Sep 2013

Cited by 51 | Viewed by 11292

Abstract

Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor [...] Read more.

Pancreatic adenocarcinoma displays a variety of molecular changes that evolve exponentially with time and lead cancer cells not only to survive, but also to invade the surrounding tissues and metastasise to distant sites. These changes include: genetic alterations in oncogenes and cancer suppressor genes; changes in the cell cycle and pathways leading to apoptosis; and also changes in epithelial to mesenchymal transition. The most common alterations involve the epidermal growth factor receptor (EGFR) gene, the HER2 gene, and the K-ras gene. In particular, the loss of function of tumor-suppressor genes has been documented in this tumor, especially in CDKN2a, p53, DPC4 and BRCA2 genes. However, other molecular events involved in pancreatic adenocarcinoma pathogenesis contribute to its development and maintenance, specifically epigenetic events. In fact, key tumor suppressors that are well established to play a role in pancreatic adenocarcinoma may be altered through hypermethylation, and oncogenes can be upregulated secondary to permissive histone modifications. Indeed, factors involved in tumor invasiveness can be aberrantly expressed through dysregulated microRNAs. This review summarizes current knowledge of pancreatic carcinogenesis from its initiation within a normal cell until the time that it has disseminated to distant organs. In this scenario, highlighting these molecular alterations could provide new clinical tools for early diagnosis and new effective therapies for this malignancy. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Emerging Roles of Claudins in Human Cancer

by Mi Jeong Kwon

Int. J. Mol. Sci. 2013, 14(9), 18148-18180; https://doi.org/10.3390/ijms140918148 - 4 Sep 2013

Cited by 159 | Viewed by 10630

Abstract

Claudins are major integral membrane proteins of tight junctions. Altered expression of several claudin proteins, in particular claudin-1, -3, -4 and -7, has been linked to the development of various cancers. Although their dysregulation in cancer suggests that claudins play a role in [...] Read more.

Claudins are major integral membrane proteins of tight junctions. Altered expression of several claudin proteins, in particular claudin-1, -3, -4 and -7, has been linked to the development of various cancers. Although their dysregulation in cancer suggests that claudins play a role in tumorigenesis, the exact underlying mechanism remains unclear. The involvement of claudins in tumor progression was suggested by their important role in the migration, invasion and metastasis of cancer cells in a tissue-dependent manner. Recent studies have shown that they play a role in epithelial to mesenchymal transition (EMT), the formation of cancer stem cells or tumor-initiating cells (CSCs/TICs), and chemoresistance, suggesting that claudins are promising targets for the treatment of chemoresistant and recurrent tumors. A recently identified claudin-low breast cancer subtype that is characterized by the enrichment of EMT and stem cell-like features is significantly associated with disease recurrence, underscoring the importance of claudins as predictors of tumor recurrence. The critical role of epigenetic mechanisms in the regulation of claudin expression indicates the possible application of epigenetic therapy to target claudins. A better understanding of the emerging role of claudins in CSC/TICs and chemoresistance may help to develop therapies against recurrent cancers. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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The Role of Thyroid Hormone Signaling in the Prevention of Digestive System Cancers

by Adam R. Brown, Rosalia C. M. Simmen and Frank A. Simmen

Int. J. Mol. Sci. 2013, 14(8), 16240-16257; https://doi.org/10.3390/ijms140816240 - 6 Aug 2013

Cited by 41 | Viewed by 9341

Abstract

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin α_Vβ₃. Systemic thyroid hormone levels are controlled [...] Read more.

Thyroid hormones play a critical role in the growth and development of the alimentary tract in vertebrates. Their effects are mediated by nuclear receptors as well as the cell surface receptor integrin α_Vβ₃. Systemic thyroid hormone levels are controlled via activation and deactivation by iodothyronine deiodinases in the liver and other tissues. Given that thyroid hormone signaling has been characterized as a major effector of digestive system growth and homeostasis, numerous investigations have examined its role in the occurrence and progression of cancers in various tissues of this organ system. The present review summarizes current findings regarding the effects of thyroid hormone signaling on cancers of the esophagus, stomach, liver, pancreas, and colon. Particular attention is given to the roles of different thyroid hormone receptor isoforms, the novel integrin α_Vβ₃ receptor, and thyroid hormone-related nutrients as possible protective agents and therapeutic targets. Future investigations geared towards a better understanding of thyroid hormone signaling in digestive system cancers may provide preventive or therapeutic strategies to diminish risk, improve outcome and avert recurrence in afflicted individuals. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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Targeting Signaling Pathways in Epithelial Ovarian Cancer

by Elisabeth Smolle, Valentin Taucher, Martin Pichler, Edgar Petru, Sigurd Lax and Johannes Haybaeck

Int. J. Mol. Sci. 2013, 14(5), 9536-9555; https://doi.org/10.3390/ijms14059536 - 2 May 2013

Cited by 53 | Viewed by 15263

Abstract

Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are [...] Read more.

Ovarian carcinoma (OC) is the most lethal gynecological malignancy. Response to platinum-based chemotherapy is poor in some patients and, thus, current research is focusing on new therapy options. The various histological types of OC are characterized by distinctive molecular genetic alterations that are relevant for ovarian tumorigenesis. The understanding of these molecular pathways is essential for the development of novel therapeutic strategies. Purpose: We want to give an overview on the molecular genetic changes of the histopathological types of OC and their role as putative therapeutic targets. In Depth Review of Existing Data: In 2012, the vascular endothelial growth factor (VEGF) inhibitor, bevacizumab, was approved for OC treatment. Bevacizumab has shown promising results as single agent and in combination with conventional chemotherapy, but its target is not distinctive when analyzed before treatment. At present, mammalian target of rapamycin (mTOR) inhibitors, poly-ADP-ribose polymerase (PARP) inhibitors and components of the EGFR pathway are in the focus of clinical research. Interestingly, some phytochemical substances show good synergistic effects when used in combination with chemotherapy. Conclusion: Ongoing studies of targeted agents in conjunction with chemotherapy will show whether there are alternative options to bevacizumab available for OC patients. Novel targets which can be assessed before therapy to predict efficacy are needed. The assessment of therapeutic targets is continuously improved by molecular pathological analyses on tumor tissue. A careful selection of patients for personalized treatment will help to reduce putative side effects and toxicity. Full article

(This article belongs to the Special Issue Molecular Bases of Cancer Research)

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