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Adrenocortical carcinoma (ACC) lacks diagnostic and prognostic biomarkers to guide treatment. A consistently dysregulated pathway in ACC is the IGF signaling pathway, specifically overexpression of IGF2, IGF-I-receptor, and IGFBP2. The objective of this study was to perform a comprehensive analysis of serum IGF and IGFBP levels and to determine their utility as diagnostic and prognostic biomarkers in ACC. Preoperative serum samples from 53 patients who underwent surgery for adrenocortical adenomas, 3 patients who underwent initial surgery for ACC, 16 patients who underwent reoperative surgery for ACC, and 5 healthy volunteer controls were analyzed. The serum concentration of IGF1, IGF2, IGFBP1, IGFBP2, and IGFBP3 was determined by enzyme-linked immunosorbent assay. No difference in the levels of IGF2 (p = .231) and IGFBP2 (p = .511) was observed between patients with ACC, benign adrenocortical tumors, and healthy volunteers. IGF1, IGFBP1, and IGFBP3 levels were not detected. High IGFBP2 levels were associated with better overall survival (OS) (p = .001) and showed a trend toward better abdominal progression-free (APFS) survival (p = .070) in patients with ACC. A subanalysis of patients undergoing reoperation for recurrent ACC showed better OS with high levels of IGFBP2 (p = .003) and a trend toward better APFS (p = .107). There was no significant difference in IGF2 and IGFBP2 levels by extent of disease. IGF2 and IGFBP2 are not elevated in the serum of patients with ACC compared with patients with benign neoplasms and healthy volunteers. Elevated serum IGFBP2 is associated with better survival in patients with ACC and those undergoing reoperative surgery for recurrent ACC.

The epithelial–mesenchymal transition (EMT), considered essential for metastatic cancer, has been a focus of much research, but important questions remain. Here, we show that silencing or removing H2A.X, a histone H2A variant involved in cellular DNA repair and robust growth, induces mesenchymal-like characteristics including activation of EMT transcription factors, Slug and ZEB1, in HCT116 human colon cancer cells. Ectopic H2A.X re-expression partially reverses these changes, as does silencing Slug and ZEB1. In an experimental metastasis model, the HCT116 parental and H2A.X-null cells exhibit a similar metastatic behaviour, but the cells with re-expressed H2A.X are substantially more metastatic. We surmise that H2A.X re-expression leads to partial EMT reversal and increases robustness in the HCT116 cells, permitting them to both form tumours and to metastasize. In a human adenocarcinoma panel, H2A.X levels correlate inversely with Slug and ZEB1 levels. Together, these results point to H2A.X as a regulator of EMT., The histone H2A variants are involved in DNA repair, gene regulation and cancer development. In this study, the authors unravel an additional role for H2A.X in the regulation of mesenchymal-like traits and activation of the EMT transcription factors, Slug and ZEB1, in colon cancer cells.

Activated Ras oncogene induces DNA-damage response by triggering reactive oxygen species (ROS) production and this is critical for oncogene-induced senescence. Until now, little connections between oncogene expression, ROS-generating NADPH oxidases and DNA-damage response have emerged from different studies. Here we report that H-RasV12 positively regulates the NADPH oxidase system NOX4-p22(phox) that produces H(2)O(2). Knocking down the NADPH oxidase with small interference RNA decreases H-RasV12-induced DNA-damage response detected by γ-H2A.X foci analysis. Using HyPer, a specific probe for H(2)O(2), we detected an increase in H(2)O(2) in the nucleus correlated with NOX4-p22(phox) perinuclear localization. DNA damage response can be caused not only by H-RasV12-driven accumulation of ROS but also by a replicative stress due to a sustained oncogenic signal. Interestingly, NOX4 downregulation by siRNA abrogated H-RasV12 regulation of CDC6 expression, an essential regulator of DNA replication. Moreover, senescence markers, such as senescence-associated heterochromatin foci, PML bodies, HP1β foci and p21 expression, induced under H-RasV12 activation were decreased with NOX4 inactivation. Taken together, our data indicate that NADPH oxidase NOX4 is a critical mediator in oncogenic H-RasV12-induced DNA-damage response and subsequent senescence.

There have been striking changes in the epidemiology of thyroid cancer worldwide with higher incidence rates, with low-risk or clinically less significant papillary thyroid cancer accounting for more than 80 % of new cases each year [1, 2]. During this change in epidemiology, our knowledge in the genetic and genomic alterations associated with thyroid cancer initiation and or progression has also expanded tremendously [3]. As precision medicine is becoming a reality for some solid malignancies, the application of new knowledge to the management of thyroid cancer is going to be imperative to precisely treat patients based on the genetics/genomics of their tumor, especially when it is found to be associated with disease behavior [4]. The study by Passon and colleagues from Italy reports new findings based on a careful analysis of 27 papillary thyroid cancer samples using high-resolution comparative genomic hybridization [5]. The investigators found that genomic amplifications were higher in high/intermediaterisk group tumors and that genomic deletions were higher in low-risk tumors based on the American Thyroid Association (ATA) risk stratification system. Several of these genomic amplifications and deletions were recurrent (occurred in more than 20 % of tumor samples) and several of the genes in the chromosomal loci with deletions have been implicated to be involved in thyroid cancer or their expression is dysregulated in cancer. The most frequent amplifications that were detected in 2q35, 4q26, and 4q34.1 contained FN1, PDE5A, and GALNTL6, respectively. The 2q35 locus is thought to be a breast cancer susceptibility locus, and FN1 expression was found to be restricted to thyroid cancer samples and absent in benign lesions [6, 7]. Interestingly, 60 % of the cases with 2q35 amplification were TNM Stage I according to the American Joint Committee on Cancer (AJCC) staging system, whereas more than 70 % were considered intermediate/high risk according to the ATA risk classification system. Although both systems include some of the same variables, the AJCC staging system also includes the patient’s age at diagnosis so that patients younger than 45 years even with lymph node and or distant metastases are considered as having only stage I/II disease. Also the ATA risk stratification system includes postoperative serum thyroglobulin level measurement. Thus, these factors likely explain the somewhat discrepant results. The amplification in 4q26 involving PDE5 was more prevalent in intermediate/highrisk cancers. Interestingly, studies have shown that tumors with high expression level of PDE5 have lower mRNA expression of differentiation markers or thyroid-specific genes (TG, TSHR, TPO, and NIS) [8]. Thus, PDE5 could be involved in thyroid cancer initiation, progression, or even radioiodine resistance. The authors also investigated the BRAF mutation status in the tumors analyzed but found no significant association with genomic amplifications or deletions. Most, but not all, studies have suggested that papillary thyroid cancers with BRAF mutations are more aggressive and that it is one of the most frequent genetic alterations in papillary thyroid cancer [3, 9]. Passon and colleague did find that 8 of the BRAF V600E mutant samples were in patients with ATA intermediate-risk papillary thyroid cancers. It would be interesting to know if the genomic deletion status in addition to BRAF mutation status could better stratify ATA low-risk from intermediate/high-risk papillary thyroid cancer or even outperform & Electron Kebebew kebebewe@mail.nih.gov

Activated toll-like receptor (TLR) signaling pathway has been reported in several endocrine neoplasms and has been found to be associated with the upregulation of proinflammatory cytokines. These cytokines are widely known as critical mediators of tumorigenesis. The stimulation of antitumor immunity through the activation of the TLR pathway can lead to the inhibition of the carcinogenesis process. However, TLRs have been considered as putative therapeutic target in various human cancers. A chronic inflammation in the absence of infection induces oxidative stress, DNA damage, and tissue damage promoting tumorigenesis. Thus, TLRs can be viewed as having a double-edged sword function. Accumulating evidences show the association between over-activation of TLR and cancer progression and TLRsignaling molecules are often involved in tumor progression. For example, TLR4 expression has been described in several human cancer, including intestinal [1], breast, and prostate cancers [2, 3] and TLR3 in papillary thyroid cancer and cervical carcinoma [4]. Several studies support that TLR activation via TLR-adaptors such as MyD88 induces NFkB translocation to the nucleus. This induces proinflammatory cytokine secretion (IL6 and IL1), antiapoptotic factors (Bcl-XL, cIAP1, ABL), as well as, pro-angiogenic factors expression (VEGF). High expression of TLR3 has been reported in a papillary thyroid cancer cell line which is consistent with its overexpression in human papillary thyroid cancer in vivo [5]. As one of the main mediator of lipopolysaccharide action, the lack or overexpression of TLR4 has also been associated with aggressive follicular thyroid cancers [6]. In this issue of Endocrine, Kim et al. [7] report that single nucleotide polymorphism (SNP) in TLR10 is associated with tumor size in patients with papillary thyroid cancer. TLR-1-TLR6-TLR-10 is located on the same chromosome and forms a cluster, and thus was the rationale for the authors to analyze these three TLR SNPs. They found that only a missense SNP in TLR10 (rs11466653, Met326Thr) showed a significant association with small tumor size (\1 cm). SNPs in the TLR-1-TLR6-TLR-10 cluster have been associated with increased risk of prostate cancer [8]. Altered TLR-10 signaling in papillary thyroid cancer may be involved in the interplay between inflammation and tumorigenesis. For example, it has been shown by several groups that IL-6, IL-1, and VEGFA are important cytokines in thyroid carcinogenesis [9–11]. Most importantly, common somatic mutations in papillary thyroid cancer such us RET/PTC rearrangements and BRAF are involved in inflammation, where they have been shown to be involved in inflammatory response and in the infiltration of innate suppressive inflammatory cells in papillary thyroid cancer [12]. Thus, a cooperation of dysregulated TLR signaling pathway in the inflammatory response of microcarcinoma seems plausible. Based on our current knowledge, TLR-10 expression seems to be restricted to immune cells like B cells or dendritic cells. Lymphocytic and dendritic cell infiltration is higher in patients with papillary thyroid cancer as compared to those with benign thyroid tumors [13]. Thus, the missense TLR-10 SNP reported by Kim and colleagues may influence the amount of lymphocytic infiltration in patients with small papillary thyroid cancer. Although lymph node metastasis and multifocality are important M. Boufraqech C. Fassassi E. Kebebew (&) Endocrine Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, 10 Center Drive, Room 4-5952, Bethesda, MD 20892, USA e-mail: kebebewe@mail.nih.gov