SUMMARYMetastasis is the primary cause of cancer-related deaths. While The Cancer Genome Atlas (TCGA) has sequenced primary tumor types obtained from surgical resections, much less comprehensive molecular analysis is available from clinically acquired metastatic cancers. Here, we perform whole exome and transcriptome sequencing of 500 adult patients with metastatic solid tumors of diverse lineage and biopsy site. The most prevalent genes somatically altered in metastatic cancer included TP53, CDKN2A, PTEN, PIK3CA, and RB1. Putative pathogenic germline variants were present in 12.2% of cases of which 75% were related to defects in DNA repair. RNA sequencing complemented DNA sequencing for the identification of gene fusions, pathway activation, and immune profiling. Integrative sequence analysis provides a clinically relevant, multi-dimensional view of the complex molecular landscape and microenvironment of metastatic cancers.

The spread of cancer throughout the body is driven by circulating tumour cells (CTCs)1. These cells detach from the primary tumour and move from the blood stream to a new site of subsequent tumour growth. They also carry information about the primary tumour and have the potential to be valuable biomarkers for disease diagnosis and progression, and for the molecular characterization of certain biological properties of the tumour. However, the limited sensitivity and specificity of current methods to measure and study these cells in patient blood samples prevent the realization of their full clinical potential. The use of microfluidic devices is a promising method for isolating CTCs2, 3; however, the devices are reliant on three-dimensional structures, which limit further characterization and expansion of cells on the chip. Here we demonstrate an effective approach to isolate CTCs from blood samples of pancreatic, breast and lung cancer patients, by using functionalised graphene oxide nanosheets on a patterned gold surface. CTCs were captured with high sensitivity at low concentration of target cells (73% ± 32.4 at 3–5 cells/mL blood).

No abstract

The addition of induction chemotherapy to concurrent chemoradiotherapy added toxicity and provided no survival benefit over concurrent chemoradiotherapy alone. The median survival achieved in each of the treatment groups is low, and the routine use of weekly carboplatin and paclitaxel with simultaneous radiotherapy should be re-examined.

MET receptor tyrosine kinase and its ligand hepatocyte growth factor (HGF) regulate a variety of cellular functions, many of which can be dysregulated in human cancers. Activated MET signaling can lead to cell motility and scattering, angiogenesis, proliferation, branching morphogenesis, invasion, and eventual metastasis. We performed systematic analysis of the expression of the MET receptor and its ligand HGF in tumor tissue microarrays (TMA) from human solid cancers. Standard immunohistochemistry and a computerized automated scoring system were used. DNA sequencing for MET mutations in both non-kinase and kinase domains was also performed. MET was differentially overexpressed in human solid cancers. The ligand HGF was widely expressed in both tumor, primarily intra-tumoral, and non-malignant tissues. The MET/HGF likely is functional and may be activated in autocrine fashion in vivo. MET and SCF were found to be positively stained in the bronchioalevolar junctions of lung tumors. A number of novel mutations of MET were identified, particularly in the extracellular semaphorin domain and the juxtamembrane domain. MET-HGF pathway can be assayed in TMAs and is often overexpressed in a wide variety of human solid cancers. MET can be activated through overexpression, mutation, or autocrine signaling in malignant cells. Mutations in the non-kinase regions of MET might play important role in tumorigenesis and tumor progression. MET would be an important therapeutic anti-tumor target to be inhibited, and in lung cancer, MET may represent a cancer early progenitor cell marker.

Growing evidence suggests that survivin expression in cancer cell nuclei may represent an important prognostic marker to predict disease outcome for cancer patients. Current reports in this research area, however, are inconsistent and propose opposing conclusions regarding the significance and prognostic value of survivin nuclear expression. The aim of our study is to review and discuss the data reported in the original publications. We have also provided new experimental data to support our view regarding the possible reasons for the observed inconsistencies in the literature. This would alert researchers to pay attention to potential pitfalls in the determination of nuclear or cytoplasmic expression of survivin for the future. © 2004 Wiley-Liss, Inc. Key words: survivin expression; cancer; cytoplasmic; nuclear; immunohistochemistry; prognostic marker Among the 19 publications relevant to survivin localization in nuclei or cytoplasm in various cancer tissues, 9 showed that the expression of survivin in cancer cell nuclei is an unfavorable prognostic marker, 1-10 whereas studies from 5 of 19 proposed an opposing notion that the nuclear expression of survivin represented a favorable prognostic marker. 10 -14 The remaining 5 publications did not focus on studying the significance of nuclear expression of survivin in disease outcome, although these reports pointed out the fact that survivin could be expressed in either cytoplasm or nuclei. [15][16][17][18][19] Two of these 5 studies reported that overall, survivin expression was an unfavorable prognostic factor. 16,18 The localization of survivin in nuclei or cytoplasm was determined by immunohistochemistry (IHC) in all 19 reports. One of the 19 publications alternatively carried out Western blots using cell lysates from the fractionated cytoplasm and nuclei for the confirmation of survivin localization. 5 In addition, Nakagawa et al. 20 reported recently that nuclear localization of survivin, as well as cytoplasmic in some cases, was essentially found in acute lymphocytic leukemia (ALL) cells whereas cytoplasmic expression of survivin was predominantly showed in chronic lymphocytic leukemia (CLL) cells. The significance, however, was not investigated. Nuclear expression of survivin is an unfavorable prognostic markerIn hepatocellular carcinoma (HCC), studies from Ito et al. 1 indicated that 14 of 20 (70%) HCC tissues showed nuclear staining of survivin, whereas non-tumor tissues showed little survivin staining. Nuclear survivin expression strongly correlated with the proliferation index. 1 Similarly, studies from Moon et al. 4 showed that 22 of 35 (63%) survivin-positive specimens (total ϭ 47) showed punctate nuclear staining in HCC cells. In contrast, nonmalignant hepatocytes showed only cytoplasmic staining. HCC specimens with nuclear survivin expression showed the highest PCNA (proliferating cell nuclear antigen) labeling index and correlated with tumor cell de-differentiation. 4 Recently, Fields et al. 8 reported that immunohistochemical analyses of 72 hep...

Reactive oxygen species (ROS) are important signaling molecules in cancer. The level of ROS will determine physiological effects. While high levels of ROS can cause damage to tissues and cell death, low levels of ROS can have a proliferative effect. ROS are produced by tumor cells but also cellular components that make up the tumor microenvironment (TME). In this review, we discuss the mechanisms by which ROS can affect the TME with particular emphasis on tumor-infiltrating leukocytes. Greater insight into ROS biology in this setting may allow for therapeutic manipulation of ROS levels in order to remodel the tumor microenvironment and increase anti-tumor activity.

No abstract