β2-Microglobulin Induces Epithelial to Mesenchymal Transition and Confers Cancer Lethality and Bone Metastasis in Human Cancer Cells
Bone metastasis is one of the predominant causes of cancer lethality. This study demonstrates for the first time how β2-microglobulin (β2-M) supports lethal metastasis in vivo in human prostate, breast, lung, and renal cancer cells. β2-M mediates this process by activating epithelial to mesenchymal transition (EMT) to promote lethal bone and soft tissue metastases in host mice. β2-M interacts with its receptor, hemochromatosis (HFE) protein, to modulate iron responsive pathways in cancer cells. Inhibition of either β2-M or HFE results in reversion of EMT. These results demonstrate the role of β2-M in cancer metastasis and lethality. Thus, β2-M and its downstream signaling pathways are promising prognostic markers of cancer metastases and novel therapeutic targets for cancer therapy. Cancer Res; 71(7); 2600–10. ©2011 AACR
Recent Advances in Cancer Therapy: An Overview
Abstract:
The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.
Authors: Urruticoechea, A.1; Alemany, R.1; Balart, J.1; Villanueva, A.1; Vinals, F.1; Capella, G.1
Source: Current Pharmaceutical Design, Volume 16, Number 1, January 2010 , pp. 3-10(8)
The landscape of cancer treatment has dramatically changed over the last four decades. The age when surgery and radiotherapy were the only effective way to fight tumour growth has ended. A complex scenario where the molecular features of tumours seem to be the cornerstone of any therapy is now emerging. Here we provide an overview on the different approaches to cancer treatment. This review will help the reader to acknowledge the pivotal role of some classic cancer therapies, including surgery, radiation, chemotherapy and endocrine therapy, now better understood in the mechanims underpinning their efficacy. Following, we focus on the understanding of the value of systemic treatment and on an up-date on the novel, up-coming therapies of the current targeted therapy age, including new antibodies, small molecules, antiangiogenics and viral therapy. We briefly elaborate, finally, on new biomarkers development and how it should rule and determine the future of therapeutic research in cancer.
Authors: Urruticoechea, A.1; Alemany, R.1; Balart, J.1; Villanueva, A.1; Vinals, F.1; Capella, G.1
Source: Current Pharmaceutical Design, Volume 16, Number 1, January 2010 , pp. 3-10(8)
Bone-Marker Levels
Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada.
Milton S. Hershey Medical Center, Pennsylvania State University Cancer Institute, Hershey, Pennsylvania, USA.
The skeleton is typically the first site of metastasis in patients with prostate cancer, and bone metastases can result in severe bone pain and potentially debilitating fractures. Although bone scans are a reliable means of assessing osteoblastic lesions, tools for monitoring early changes in bone health are lacking. Biochemical markers of bone turnover might fulfill this unmet need.
Correlative studies have suggested that bone-marker levels may have utility in assessing disease progression and response to bone-directed therapy. Elevated levels of the markers, N-telopeptide of type I collagen and bone-specific alkaline phosphatase, are associated with higher rates of death and skeletal-related events in the bone metastasis setting. Marker levels also correlate with response to zoledronic acid treatment, and similar data with the investigational agent, denosumab, are emerging.
Changes in bone-marker levels reflect alterations in skeletal homeostasis and can provide important insights into bone disease progression and response to bone-directed therapy in patients with prostate cancer. More mature data from currently ongoing clinical trials will provide further insight on the utility of marker assessments as an adjunct to established monitoring methods in prostate cancer.
Written by:
Saad F, Lipton A
Milton S. Hershey Medical Center, Pennsylvania State University Cancer Institute, Hershey, Pennsylvania, USA.
The skeleton is typically the first site of metastasis in patients with prostate cancer, and bone metastases can result in severe bone pain and potentially debilitating fractures. Although bone scans are a reliable means of assessing osteoblastic lesions, tools for monitoring early changes in bone health are lacking. Biochemical markers of bone turnover might fulfill this unmet need.
Correlative studies have suggested that bone-marker levels may have utility in assessing disease progression and response to bone-directed therapy. Elevated levels of the markers, N-telopeptide of type I collagen and bone-specific alkaline phosphatase, are associated with higher rates of death and skeletal-related events in the bone metastasis setting. Marker levels also correlate with response to zoledronic acid treatment, and similar data with the investigational agent, denosumab, are emerging.
Changes in bone-marker levels reflect alterations in skeletal homeostasis and can provide important insights into bone disease progression and response to bone-directed therapy in patients with prostate cancer. More mature data from currently ongoing clinical trials will provide further insight on the utility of marker assessments as an adjunct to established monitoring methods in prostate cancer.
Written by:
Saad F, Lipton A
Effects of distant metastasis and peripheral CA 15-3 on the induction of spontaneous T cell responses in breast cancer patients
Abstract Tumor-specific memory T cells are detectable in the bone marrow (BM) of a majority of breast cancer patients. In vitro they can be reactivated to IFN-γ producing, cytotoxic effector cells and reject autologous, xenotransplanted tumors in NOD/SCID mice after specific restimulation with autologous dendritic cells (DC). In this study, we demonstrate the presence of specific tumor-reactive BM memory T cells in altogether 56 out of 129 primarily operated breast cancer patients by short-term IFN-γ EliSpot assays with unstimulated T cells and tumor antigen presenting, autologous DCs.
We observed tumor-reactive BM memory T cells predominantly in patients with primarily metastatic disease (P = 0.011) or with increased concentrations of tumor marker CA 15-3 in the peripheral blood (P = 0.004), respectively. Memory T cell reactivity against HLA-A*0201-restricted peptides from the tumor-associated antigens MUC1, Hpa16–24 and Hpa183–191 was also detected particularly in patients with elevated peripheral CA 15-3 concentrations (P < 0.05). Altogether these data indicate that the systemic presence of tumor-derived antigens promotes an induction of tumor-specific cellular immune responses in the human BM
Christoph Domschke1 , Florian Schuetz1, Nora Sommerfeldt2, Joachim Rom1, Alexander Scharf1, Christof Sohn1, Andreas Schneeweiss1 and Philipp Beckhove2
(1) Department of Gynecology and Obstetrics, University Hospital of Heidelberg, Voßstraße 9, 69115 Heidelberg, Germany
(2) Tumor Immunology Program, Division of Translational Immunology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany
We observed tumor-reactive BM memory T cells predominantly in patients with primarily metastatic disease (P = 0.011) or with increased concentrations of tumor marker CA 15-3 in the peripheral blood (P = 0.004), respectively. Memory T cell reactivity against HLA-A*0201-restricted peptides from the tumor-associated antigens MUC1, Hpa16–24 and Hpa183–191 was also detected particularly in patients with elevated peripheral CA 15-3 concentrations (P < 0.05). Altogether these data indicate that the systemic presence of tumor-derived antigens promotes an induction of tumor-specific cellular immune responses in the human BM
Christoph Domschke1 , Florian Schuetz1, Nora Sommerfeldt2, Joachim Rom1, Alexander Scharf1, Christof Sohn1, Andreas Schneeweiss1 and Philipp Beckhove2
(1) Department of Gynecology and Obstetrics, University Hospital of Heidelberg, Voßstraße 9, 69115 Heidelberg, Germany
(2) Tumor Immunology Program, Division of Translational Immunology, German Cancer Research Center (DKFZ), INF 280, 69120 Heidelberg, Germany
Epigenetic Profiles Distinguish Malignant Pleural Mesothelioma from Lung Adenocarcinoma
Cancer Research, 10.1158/0008-5472.CAN-09-1595
Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively.
Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease.
Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):OF1–10]
Yasuhiro Goto1, Keiko Shinjo1,3, Yutaka Kondo1, Lanlan Shen7, Minoru Toyota8, Hiromu Suzuki9, Wentao Gao10, Byonggu An1, Makiko Fujii1, Hideki Murakami1, Hirotaka Osada1,3, Tetsuo Taniguchi5, Noriyasu Usami5, Masashi Kondo4, Yoshinori Hasegawa4, Kaoru Shimokata11, Keitaro Matsuo2, Toyoaki Hida6, Nobukazu Fujimoto12, Takumi Kishimoto12, Jean-Pierre J. Issa7 and Yoshitaka Sekido1,3
Divisions of 1 Molecular Oncology and 2 Epidemiology and Prevention, Aichi Cancer Center Research Institute; Departments of 3 Cancer Genetics and 4 Respiratory Medicine and 5 Division of General Thoracic Surgery, Nagoya University Graduate School of Medicine; 6 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 7 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 8 Department of Biochemistry and 9 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; 10 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 11 Department of Biomedical Sciences, Chubu University, Kasugai, Japan; and 12 Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan
Key Words: DNA methylation • histone H3 lysine 27 trimethylation • malignant pleural mesothelioma • microarray
Malignant pleural mesothelioma (MPM) is a fatal thoracic malignancy, the epigenetics of which are poorly defined. We performed high-throughput methylation analysis covering 6,157 CpG islands in 20 MPMs and 20 lung adenocarcinomas. Newly identified genes were further analyzed in 50 MPMs and 56 adenocarcinomas via quantitative methylation-specific PCR. Targets of histone H3 lysine 27 trimethylation (H3K27me3) and genetic alterations were also assessed in MPM cells by chromatin immunoprecipitation arrays and comparative genomic hybridization arrays. An average of 387 genes (6.3%) and 544 genes (8.8%) were hypermethylated in MPM and adenocarcinoma, respectively.
Hierarchical cluster analysis showed that the two malignancies have characteristic DNA methylation patterns, likely a result of different pathologic processes. In MPM, a separate subset of genes was silenced by H3K27me3 and could be reactivated by treatment with a histone deacetylase inhibitor alone. Integrated analysis of these epigenetic and genetic alterations revealed that only 11% of heterozygously deleted genes were affected by DNA methylation and/or H3K27me3 in MPMs. Among the DNA hypermethylated genes, three (TMEM30B, KAZALD1, and MAPK13) were specifically methylated only in MPM and could serve as potential diagnostic markers. Interestingly, a subset of MPM cases (4 cases, 20%) had very low levels of DNA methylation and substantially longer survival, suggesting that the epigenetic alterations are one mechanism affecting progression of this disease.
Our findings show a characteristic epigenetic profile of MPM and uncover multiple distinct epigenetic abnormalities that lead to the silencing of tumor suppressor genes in MPM and could serve as diagnostic or prognostic targets. [Cancer Res 2009;69(23):OF1–10]
Yasuhiro Goto1, Keiko Shinjo1,3, Yutaka Kondo1, Lanlan Shen7, Minoru Toyota8, Hiromu Suzuki9, Wentao Gao10, Byonggu An1, Makiko Fujii1, Hideki Murakami1, Hirotaka Osada1,3, Tetsuo Taniguchi5, Noriyasu Usami5, Masashi Kondo4, Yoshinori Hasegawa4, Kaoru Shimokata11, Keitaro Matsuo2, Toyoaki Hida6, Nobukazu Fujimoto12, Takumi Kishimoto12, Jean-Pierre J. Issa7 and Yoshitaka Sekido1,3
Divisions of 1 Molecular Oncology and 2 Epidemiology and Prevention, Aichi Cancer Center Research Institute; Departments of 3 Cancer Genetics and 4 Respiratory Medicine and 5 Division of General Thoracic Surgery, Nagoya University Graduate School of Medicine; 6 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan; 7 Department of Leukemia, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 8 Department of Biochemistry and 9 First Department of Internal Medicine, Sapporo Medical University, Sapporo, Japan; 10 Department of General Surgery, First Affiliated Hospital of Nanjing Medical University, Nanjing, China; 11 Department of Biomedical Sciences, Chubu University, Kasugai, Japan; and 12 Department of Respiratory Medicine, Okayama Rosai Hospital, Okayama, Japan
Key Words: DNA methylation • histone H3 lysine 27 trimethylation • malignant pleural mesothelioma • microarray
Lymph node density is a significant predictor of outcome in patients with oral cancer
BACKGROUND:: The impact of lymph node metastases on prognosis in patients with oral cavity squamous cell carcinoma (OSCC) has been well recognized. However, accurate stratification of risk for recurrence among patients with lymph node metastases is difficult based on the existing staging systems. In the current study, the utility of lymph node density (LND) was evaluated as an alternative method for predicting survival.
METHODS:: Three hundred eighty-six patients who underwent neck dissection were included. The median follow-up was 67 months. Five-year overall survival (OS), disease-specific survival (DSS), and locoregional failure (LRF) rates were calculated using the Kaplan-Meier method. LND (number of positive lymph nodes/total number of excised lymph nodes) and tumor-node-metastasis (TNM) staging variables were subjected to multivariate analysis.
RESULTS:: Using the median (LND = 0.06) as the cutoff point, LND was found to be significantly associated with outcome. For patients with LND 0.06 (P < .001). Similarly, the DSS for patients with LND 0.06 (P < .001). On univariate analysis, pathologic T and N classification, extracapsular spread, and LND were found to be significant predictors of outcome (P < .001). However, on multivariate analysis, LND remained the only independent predictor of OS (P = .02; hazards ratio, 2.0), DSS (P = .02; hazards ratio, 2.3), and LRF (P = .005; hazards ratio, 4.1). LND was also found to be the only significant predictor of outcome in patients receiving adjuvant radiotherapy (P < .05). Within individual subgroups of pN1 or pN2 patients, LND reliably stratified patients according to their risk of failure (P < .05).
CONCLUSIONS:: After surgery for OSCC, pathologic evaluation of the neck using LND was found to reliably stratify the risk of disease recurrence and survival. Cancer 2009. (c) 2009 American Cancer Society.
Gil Z, Carlson DL, Boyle JO, Kraus DH, Shah JP, Shaha AR, Singh B, Wong RJ, Patel SG.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
METHODS:: Three hundred eighty-six patients who underwent neck dissection were included. The median follow-up was 67 months. Five-year overall survival (OS), disease-specific survival (DSS), and locoregional failure (LRF) rates were calculated using the Kaplan-Meier method. LND (number of positive lymph nodes/total number of excised lymph nodes) and tumor-node-metastasis (TNM) staging variables were subjected to multivariate analysis.
RESULTS:: Using the median (LND = 0.06) as the cutoff point, LND was found to be significantly associated with outcome. For patients with LND 0.06 (P < .001). Similarly, the DSS for patients with LND 0.06 (P < .001). On univariate analysis, pathologic T and N classification, extracapsular spread, and LND were found to be significant predictors of outcome (P < .001). However, on multivariate analysis, LND remained the only independent predictor of OS (P = .02; hazards ratio, 2.0), DSS (P = .02; hazards ratio, 2.3), and LRF (P = .005; hazards ratio, 4.1). LND was also found to be the only significant predictor of outcome in patients receiving adjuvant radiotherapy (P < .05). Within individual subgroups of pN1 or pN2 patients, LND reliably stratified patients according to their risk of failure (P < .05).
CONCLUSIONS:: After surgery for OSCC, pathologic evaluation of the neck using LND was found to reliably stratify the risk of disease recurrence and survival. Cancer 2009. (c) 2009 American Cancer Society.
Gil Z, Carlson DL, Boyle JO, Kraus DH, Shah JP, Shaha AR, Singh B, Wong RJ, Patel SG.
Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, New York
Colon cancer screening practices and disclosure
Colon cancer screening practices and disclosure after receipt of positive or inconclusive genetic test results for hereditary nonpolyposis colorectal cancer.
BACKGROUND:: Patients who receive conclusive genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) tend to adopt appropriate colorectal cancer screening behaviors and disclose their test results. However, little is known about the disclosure processes or screening behaviors of individuals who receive inconclusive genetic test results. This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received.
METHODS:: Individuals with a personal history of cancer and suspected of having HNPCC participated in genetics education and counseling, underwent HNPCC testing, and received genetic test results (GCT) within a prospective cohort study. Demographic, psychosocial, and behavioral data were obtained from questionnaires and interviews completed before and after GCT.
RESULTS:: Index cases with inconclusive genetic test results were less likely to screen within 12 months. Index cases who disclosed test results to children within 6 months were more likely to screen within 12 months, controlling for mutation status. Index cases with inconclusive genetic test results were less likely to share results with a healthcare provider within 6 months. Index cases who disclosed genetic test results to healthcare providers within 6 months were more likely to have endoscopy within 12 months.
CONCLUSIONS:: Genetic test results and disclosure significantly affected colon cancer screening at 12-month follow-up. Interventions to improve adherence to colorectal cancer screening should consider increased education of those receiving inconclusive results and encourage disclosure to healthcare providers and family members. Cancer 2009. Published 2009 by the American Cancer Society.
BACKGROUND:: Patients who receive conclusive genetic test results for hereditary nonpolyposis colorectal cancer (HNPCC) tend to adopt appropriate colorectal cancer screening behaviors and disclose their test results. However, little is known about the disclosure processes or screening behaviors of individuals who receive inconclusive genetic test results. This study compared endoscopy use and disclosure between individuals with positive and inconclusive genetic test results, within a year after results were received.
METHODS:: Individuals with a personal history of cancer and suspected of having HNPCC participated in genetics education and counseling, underwent HNPCC testing, and received genetic test results (GCT) within a prospective cohort study. Demographic, psychosocial, and behavioral data were obtained from questionnaires and interviews completed before and after GCT.
RESULTS:: Index cases with inconclusive genetic test results were less likely to screen within 12 months. Index cases who disclosed test results to children within 6 months were more likely to screen within 12 months, controlling for mutation status. Index cases with inconclusive genetic test results were less likely to share results with a healthcare provider within 6 months. Index cases who disclosed genetic test results to healthcare providers within 6 months were more likely to have endoscopy within 12 months.
CONCLUSIONS:: Genetic test results and disclosure significantly affected colon cancer screening at 12-month follow-up. Interventions to improve adherence to colorectal cancer screening should consider increased education of those receiving inconclusive results and encourage disclosure to healthcare providers and family members. Cancer 2009. Published 2009 by the American Cancer Society.
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