What's new?

Melanocortin 1 receptor (MC1R), which plays a central role in the production of melanin, is subject to marked genetic variation, with certain variants increasing melanoma risk through fair skin phenotype. Others MCR1 variants, however, influence melanoma risk through pigment-independent alterations. Such variants may include those that affect interactions between Mc1r and hepatocyte growth factor (HGF)/Met signaling, as suggested by this investigation of Mcr1 deficiency in a UV-induced melanoma mouse model. HGF has been implicated in tumor escape from B-RAF inhibitors in human melanoma, and MET is a target for melanoma therapy, suggesting potential therapeutic significance for the findings.

What's new?

More men than women get liver cancer, in part because of the protective effect of the estrogen pathway. Many women who do develop hepatocellular cancer have less estrogen receptor due to higher levels of miR-18a, which slows estrogen receptor production. In this paper, the authors asked, what causes the increase in miR-18a? They found that p53 participates in pumping out miR-18a, and further investigation revealed that tying up p53 decreased levels of miR-18a, while overexpressing p53 increased miR-18a. Samples taken from female HCC patients confirmed this association, suggesting that p53 could be a useful therapeutic target in female HCC.

What's new?

Both MEK1/2 inhibitors and interferon-γ (IFN-γ) have anti-tumorigenic activity. In this study, the authors found that the MEK1/2 inhibitor U0126 decreases growth of chemically induced pulmonary carcinomas, and increases tumor-free and survival rates in mice inoculated Lewis lung carcinomas. The authors also conclude that this anti-tumorigenic action of U0126 is due, in part, to its activation of IFN-γ production, via enhanced activity of liver X receptor (LXR).

What's new?

Mutations in PIK3CA have been identified in various cancers, including osteosarcoma, a disease for which new treatments are desperately needed. One potential therapy for osteosarcoma is BYL719, a novel agent that is active against tumor cells harboring PIK3CA variants. In the present study, BYL719 was found to inhibit the migration and decrease the proliferation of osteosarcoma cells. The drug accomplished the latter by blocking the cell cycle in G0/G1. In pre-clinical mouse models of osteosarcoma, BYL719 monotherapy significantly reduced tumor progression, tumor ectopic bone formation, and tumor vascularization. Its therapeutic potential may be augmented by combined use with ifosfamide.

What's new?

A number of proteins that are involved in tumorigenesis are influenced by the protein kinase CK2, and the expression of CK2α specifically is known to be modified in certain cancers, suggesting possible effects on tumor development and progression. The present study indicates that CK2α is an independent prognostic indicator of gastric carcinoma and is involved in tumorigenesis by regulating the phosphorylation of the potentially oncogenic protein DBC1 (deleted in breast cancer 1). Inhibition of CK2α or DBC1 attenuated proliferation and invasion activity of cancer cells, suggesting that the CK2α-DBC1 pathway may be a therapeutic target for gastric carcinoma.

What's new?

Activation of peroxisome proliferator-activated receptor γ (PPARγ) is capable of undermining certain malignant properties of gastric cancer cells in vitro, suggesting that it may be of relevance in human gastric cancers. Here, in gastric cancer cell and zebrafish models, PPARγ overexpression inhibited epithelial-mesenchymal transition and led to reductions in cell invasion and migration. The effects of PPARγ overexpression were associated with galectin-9 upregulation. In human patients with intestinal-type gastric cancer, positive PPARγ tumor status was linked to reduced overall and cancer-specific mortalities. The findings suggest that PPARγ may be a therapeutic target and prognostic factor in gastric cancer.

What's new?

IgG1 anti-EGFR monoclonal antibodies like Cetuximab are commonly used for the treatment of EGFR⁺ solid tumors. The exact mechanisms underlying anti-EGFR mAb-mediated tumor regression and the possible involvement of innate or adaptive immunity, however, remain controversial. This study provides strong evidence that IgG1 anti-EGFR mAb induce the novel mechanism of CD8⁺ T cell-mediated cytotoxicity. This knowledge may be beneficial for future approaches in cancer therapy. The study also demonstrates that novel humanized mouse models allow the preclinical testing of therapeutic mAb as well as the characterization of their functional crosstalk with human immune cells in vivo.

What's new?

While Oncostatin M was originally identified as a cytokine with anti-proliferative properties on melanoma and other solid tumor cell lines, its in vivo function remains obscure. Here the authors show that application of Oncostatin M into the trachea of mice had unexpected growth-promoting effects on lung tumors without direct pro-proliferative effects on tumor cells ex vivo. Detailed analysis implicated non-tumor cells in the process through the recruitment of tumor promoting M2-type monocytes/macrophages. This study uncovers a complex function of Oncostatin M in cancer biology and points to a specific role in lung cancer development.

What's new?

Various types of gastrointestinal (GI) cancers display similar epigenetic aberrations. In this study, the authors examined a number of genes that have been shown to have altered methylation in cholangiocarcinoma, to see whether these genes might also be altered in other GI cancers. They found five genes that are frequently methylated in colorectal, pancreatic, and gastric cancer and cholangiocarcinoma. Methylation patterns in these genes may therefore provide biomarkers that are especially promising for colorectal cancer detection, with a high combined sensitivity (95%) and specificity (98%).

What's new?

Early diagnosis can improve survival for patients with bladder cancer, but biomarkers and noninvasive tests that are sensitive enough to detect bladder tumors, and low-grade lesions in particular, are lacking. Here, following genome-wide serum miRNA analysis by Miseq sequencing in bladder cancer patients, a six-miRNA panel for diagnosis was developed. The panel was based on a multivariate logistic regression model and showed higher sensitivity than urine cytology in bladder cancer diagnosis, especially for patients with early stage disease. Among the six miRNAs identified for the panel, miR-152 was found to independently predict recurrence in non-muscle-invasive bladder cancer.

What's new?

The use of “-omics” technologies in the investigation of tumor biomarkers has led to the generation of multiple types of data sets. But which of those sets are most useful for prognostic assessment of disease is unclear. Here, for prognostic accuracy in metastatic melanoma after resection, a combination of clinicopathologic variables and RNA expression data was found to out-perform information derived from “-omics” platforms alone. Among patients, however, the prognostic accuracy of different data types varied. The findings suggest that more data does not necessarily increase prognostic accuracy and that patient evaluation must rely on both traditional and novel approaches.

What's new?

The association of microRNAs (miRNAs) with cancer initiation, progression, and metastasis has fueled increasing interest in their potential as diagnostic and therapeutic markers. The current study aimed to identify an miRNA expression signature that could be used to distinguish prostate cancer from benign prostatic hyperplasia by using prostate secretions obtained from patients. MiRNAs were found to be present in the prostate secretion samples, with altered expression detected for four miRNAs in particular. The findings suggest that certain miRNAs may be powerful tools for aiding prostate cancer diagnosis.

What's New?

Blood type A indicates a higher risk of gastric cancer, but why? This study examined the relationship between blood group genes and cancer. The authors investigated 32 variants among not only the ABO alleles, but also including the genes involved in producing the Lewis blood group antigens. They confirmed blood group A as a risk factor for diffuse-type gastric cancer, and also detected an association between certain Lewis antigen alleles and intestinal-type gastric cancer. Interestingly, these alleles also popped up among controls who harbored H. pylori infection. These associations certainly warrant further investigation into their role in gastric cancer.

What's new?

Due to the potential adverse effect of cannabis smoking and its popularity, an investigation of its association with lung cancer risk is essential to help support appropriate regulations as well as health and social policy responses. The analysis presented here included the largest data set on cannabis and lung cancer risk to date. Its non-linear dose-response was examined using restricted cubic spline regression, a first in this line of work. Results provide little evidence for an increased risk of lung cancer among habitual or long-term cannabis smokers, although the possibility of potential adverse effect for heavy consumption cannot be excluded.

What's new?

Folate is essential to DNA synthesis and repair, suggesting that folate deficiency, in disrupting normal DNA processes, may facilitate the development of certain cancers, including oral and pharyngeal cancer (OPC). The relationship between folate intake and risk of OPC, however, is unclear. In this analysis of data from the International Head and Neck Cancer Epidemiology (INHANCE) Consortium, high levels of folate intake were found to be inversely associated with overall OPC risk. The association was strongest for cancer of the oral cavity. Risk of OPC was highest among heavy alcohol drinkers with low folate levels.

What's new?

One-carbon metabolism (OCM) involves the transfer of a carbon unit from methyl donor nutrients to molecules involved in the synthesis and methylation of DNA. As a result, dietary imbalances or deficiencies in nutrients crucial for OCM may affect DNA replication, repair, and regulation, potentially facilitating cancer development. This analysis of circulating levels of OCM nutrients in head and neck cancer and esophageal cancer patients and matched controls reveals an association between elevated levels of the amino acid homocysteine and increased risk of squamous cell carcinoma of the head and neck. Risk was decreased slightly by elevated folate levels.

What's new?

Substantial variation exists in the evaluation of cancer screening for pre-invasive lesions. In some instances, such as overdiagnosis in the case of nonprogressive lesions, screening may be more harmful than beneficial. The authors of this study have derived methods of estimation of sensitivity and effect, including formulae and data requirements at the level of events and person years, that are consistent with the purpose of cancer screening to prevent invasive disease. The six indicators specified in the study are useful at the levels of laboratory, clinical medicine, and public health.

What's new?

Cetuximab, an anti-EGFR monoclonal antibody (mAb), is used in combination with chemotherapy for several types of cancer. While many studies evaluating the toxicity of mAbs have focused on fatal adverse events, less severe toxic effects can still have a major impact on patient health. In this meta-analysis, the authors found that there is a slight but significant increase in the risk of severe hematologic toxicity associated with cetuximab treatment. Rigorous hematological monitoring of a patient's peripheral hemogram is therefore warranted when cetuximab is part of a treatment regimen.

What's new?

New treatment options are needed for patients with soft-tissue sarcomas (STS) as management of metastatic disease is currently not very successful. Here the authors develop a new line of treatment, where they add an oncolytic adenovirus, CGTG-102 (Ad5/3-D24-GMCSF) to doxorubicin and ifosfamide, the preferred chemotherapeutic regimen against most types of STS. They show in an immune-competent Syrian hamster model that this combination is effective against established STS tumors. In an additional line of research, doxorubicin without ifosfamide synergized with CGTG-102 to treat STS of human origin in a mouse xenograft tumor model. These results support a future clinical application of CGTG-102 in combination with doxorubicin-based chemotherapy for better treatment of STS.

What's New?

Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might be involved in aging. The linkage of TR4 to tumor progression, however, remains unclear. Here, the authors found the first clinical evidence that TR4 may be related to the prostate cancer (PCa) Gleason score. Through in vitro studies and in vivo animal studies, they showed that TR4 promotes PCa and also demonstrated CCL2/CCR2 signaling as an important mediator in TR4 action. The findings indicate TR4 as a potential key player that could be used as a biomarker or therapeutic target to battle PCa metastasis.

What's new?

Attacking cancer with viruses is an strategy that's been pursued for decades, with mixed results. This paper examined the effectiveness of combining oncolytic viral therapy with isolated limb perfusion (ILP), in which cancer at the extremities is isolated and subjected to high doses of chemotherapy. Adding virus to this treatment in rats with sarcoma improved the rats' survival compared with standard ILP, and delivering the virus by this method got more virus to the tumor than giving it intravenously. This harmonious combination boosts the effectiveness of both methods, and certainly warrants further investigation.

What's new?

While cytomegalovirus (CMV) has been functionally implicated in glioblastoma, its presence has been challenged by several reports, including lack of CMV mRNA in transcriptome studies. Here, the authors utilized deep-coverage whole-genome sequencing data to detect CMV DNA in surgically resected tumors. They found no traces of CMV in 52.6 billion DNA sequencing reads from 34 glioblastomas. Based on statistical analysis, they conclude that should the virus be present in these tumors, the average CMV level does not exceed one virus per 240,000 tumor cells (99% CI), effectively settling any remaining controversies regarding widespread presence of CMV DNA in glioblastoma.

What's New?

Granulocyte Colony Stimulating Factor (G-CSF) is known to mobilize hematopoietic progenitor stem cells in the blood of donors for stem cell transplantations, but its role as a neurotrophic factor is much less well understood. Here the authors show that G-CSF potentiates tumor growth and metastasis through autonomic nerve development in prostate tumors. This raises concerns regarding the use of G-CSF in cancer patients and gives insight into the interplay between tumor nerve development and growth factors as a potential new target in cancer therapy.

What's new?

Fatty liver is associated with hepatocellular carcinoma (HCC), but its exact role has been unclear. In this study, the authors found that HCC metastasis was increased in rats whose livers were steatotic. They also found that when hepatic stellate cells (HSCs) from rats with steatotic livers were co-injected with HCC cells into normal rats, the resulting tumors were significantly larger than when normal HSC cells were used. The increased levels of cytokines secreted by activated fatty-liver HSCs may enhance proliferation and migration of HCC.

What's New?

Several members of the ADAMTS family of extracellular proteinases help stave off cancer, and these genes are often silenced or altered in tumor cells. Previous work has shown that breast cancer patients whose tumours express higher levels of ADAMTS-15 have better outcomes. In this study, the authors investigated what happened when breast cancer cells lines expressed either wild-type or a metalloproteinase-deficient mutant of ADAMTS-15. They saw no effect on proliferation or apoptosis, regardless of metalloproteinase function, but both forms hampered cell migration. However, only the wild-type impeded angiogenesis. Both forms affected metastasis, but the effects varied depending on the tissue microenvironment of the target organ.

What's New

Many prostate cancers (PCa) eventually develop resistance to androgen-deprivation therapy, and the androgen receptor (AR) is known to play a critical role in this process. However, even when AR signaling is blocked, PCa tumors may still recur. Some studies have suggested that the glucocorticoid receptor (GR) might be responsible for the progression to castration-resistant prostate cancer. In this study, however, the authors determined that this is not the case. They also found that GR expression is suppressed by active AR signaling, due to a “negative androgen-response element” sequence near the GR gene.

What's new?

Metabolic enzymes play key regulatory roles in tumorigenesis, though their specific contributions to tumor cell growth and survival are unclear. This report is the first to demonstrate that phosphoserine aminotransferase 1 (PSAT1), an enzyme involved in serine biosynthesis, is overexpressed in non-small cell lung cancer (NSCLC). Elevated PSAT1 appears to enhance the proliferation of NSCLC cells by promoting cell-cycle progression, an effect associated with inhibition of cyclin D1 degradation and altered activity of the Rb-E2F pathway. The results indicate that unrestrained cell-cycle progression in NSCLC is linked to PSAT1 upregulation and constitutive activation of E2F.

What's new?

Drug resistance remains a major challenge in the management of cancer patients. Using a 3D model of tumor cells the authors identify cell crowding and the interferon response as important mediators of drug resistance. They demonstrate that interferon regulatory factor 9 (IRF9) and a panel of interferon-stimulated genes are induced by cell crowding in this model. These results link unexpected new molecular mechanisms with the therapy resistance of solid tumors.

What's new?

Epithelial-mesenchymal transition (EMT) is involved in the initiation of metastasis and is regulated by transcription factors (EMT-TFs) that are themselves regulated by miRNAs. The roles of the different EMT-TFs and their functional relationships, however, are poorly understood. Here, the EMT-TFs Snail1 and Zeb1 were found to play an essential role in EMT induction, while mesenchymal phenotype was maintained by continuous Snail1 and Snail2 expression. Snail1 controlled and maintained the mesenchymal phenotype through CpG DNA hypermethylation of miR-200 loci. Hypermethylated miR-200 family members may serve as surrogate markers in the treatment or prognosis of carcinosarcomas.

What's new?

Dendritic cells (DCs) are of great therapeutic interest, owing to their ability to induce immune responses against tumor cells. So far, however, DC-based vaccines have shown limited therapeutic effectiveness, which may be due, in part, to immune interference by tumor exosomes. Here, tumor exosomes were harnessed as a possible antigen source for DC vaccination. Survival time in tumor-bearing mice was found to be prolonged following vaccination with tumor exosome-loaded DCs. As an antigen source, tumor exosomes were superior to tumor lysate. DC loading using tumor exosomes recovered from patients could allow for individualized tumor immunotherapy.

What's new?

The infiltration of myeloid cells in human papillomavirus (HPV)-induced usual-type vulvar intraepithelial neoplasia (uVIN) may influence the uVIN microenvironment and responses to immunotherapy. In the present study, uVIN progression was characterized by increases in intraepithelial and stromal M1 and M2 macrophages and by dense intraepithelial infiltration by CD14+ macrophages. Dense CD14+ macrophage infiltration was associated with a significantly increased risk of recurrence, indicating that it is an independent prognostic factor for disease recurrence. By contrast, best recurrence free survival was associated with sparse CD14+ cell populations and an abundance of stromal CD8+TIM3+ cells.

What's new?

Immunotherapy can be an effective means of treatment in usual-type vulvar intraepithelial neoplasia (uVIN), which commonly is associated with persistent high-risk human papillomavirus (HPV) infection. However, some uVIN patients are refractory to immunotherapy, for reasons that remain unclear. In this study, increased numbers of regulatory T cells and TIM3+ T cells were detected in uVIN tissues. Dense infiltration of uVIN lesions by stromal CD8+TIM3+ and CD3+NKG2A+ T cells predicted a low recurrence rate and prolonged recurrence free survival in uVIN.

What's new?

Acidification of extracellular pH (pHe) plays an important role in promoting tumor metastasis. The present study describes a novel pH-activated near-infrared (NIR) fluorescent probe that is capable of both visualizing tumors by sensing the acidic pHe and revealing correlations between tumor metastatic potential and intratumoral acidosis. NIR fluorescence imaging with the probe uncovered acidosis distribution to the tumor periphery in highly metastatic tumors, versus a wide distribution of acidosis in tumors with reduced metastatic potential. By delineating intratumoral acidosis, the probe could facilitate the evaluation of tumor metastatic potential and assist in the optimization of treatment strategies.

What's New?

An emerging approach to metabolic imaging in cancer is based on ¹³C-hyperpolarized magnetic resonance (MR) spectroscopy. But metabolic markers specific to cancer must be identified to realize its promise. Here, metabolic conversion of hyperpolarized esters was explored as a potential means of detecting hepatocellular carcinoma (HCC). Hyperpolarized [1,3-¹³C₂]ethyl acetoacetate (EAA) was found to be an exceptionally good substrate for carboxyl esterase-1, concentrations and activities of which are altered in cancer cells. Metabolic conversion of EAA as a substrate for ¹³C-hyperpolarized MR significantly enhanced the detection of implanted liver cancer in rats.

What's new?

Tests for Epstein-Barr virus (EBV) DNA may help screen high-risk populations for nasopharyngeal carcinoma (NPC), but these tests are not very sensitive. In this study, the authors developed a panel of biomarkers that instead tests for altered methylation of tumor-suppressor genes. They found that, when plasma and swabs from early-stage NPC patients were analyzed with the methylation panel, it detected the cancer with higher sensitivity and specificity than tests for EBV DNA. Combining the two tests may enhance noninvasive screening for NPC, thus enabling more timely and effective treatments.

What's New?

Cancer is a costly disease for society, with potentially large affects on productivity and economy. According to this study, in 2008 premature cancer-related deaths in Europe resulted in lost productivity costs amounting to €75 billion. Costs were nearly twice as high for males compared with females. In addition, while impacts of specific cancers varied geographically across Europe, some of the most costly cancers included those of the lung, breast, and colorectum, with melanoma having the greatest cost per death. The findings provide insight into the societal impacts of cancer and could inform the prioritization of prevention strategies.

What's new?

Human papillomavirus type 16 (HPV16) is the most prevalent carcinogenic HPV type, but infection progresses to cervical precancer in only a small fraction of cases. Determining whether infections will progress or clear remains an elusive goal, but this study suggests that it may be possible to distinguish between the two with a bisulfite-treated DNA next-generation sequencing (NGS) assay specific to HPV16 DNA methylation. The NGS assay performed similarly to pyrosequencing and has several advantages over traditional methods. Using HPV16 CpG methylation and methyl-haplotype biomarkers, the NGS technique could aid in risk stratification for HPV-positive women.

What's new?

Evidence suggests that the development and outgrowth of hepatocellular carcinoma (HCC) is influenced by dysregulation of tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). Here, TRAIL expression was found to be reduced in about two-thirds of HCCs, based on analysis of tissue samples from patients who underwent liver resection or liver transplantation, either because of HCC or because of other liver disease. TRAIL expression was correlated with tumor size and stage, recurrence after resection, and survival rate. The findings suggest that TRAIL may be able to distinguish high-risk HCC patients and influence decisions about the need for additional perioperative adjuvant procedures.

What's new?

Sorafenib remains the standard of care for advanced hepatocellular carcinoma (HCC), despite marked variability in patient response. According to this study, a lack of response to sorafenib may be predicted by certain phenotypic signatures of liver tumor cells, specifically activation of the TGF-ß pathway, a mesenchymal phenotype, and expression of CD44. By contrast, sensitivity to sorafenib-induced apoptosis is associated with expression of the stem-related proteins EpCAM or CD133 in epithelial-like cells and knockdown of CD44 in mesenchymal-like cells. The findings suggest that CD44 targeting could be a valuable strategy to deploy in combination with sorafenib therapy.

What's New?

If you get glioblastoma, there aren't too many effective treatment options available. This study hopes to change that with a new combination therapy, called RIST (for rapamycin, irinotecan, sunitinib, temozolomide). Both rapamycin and sunitinib hamper survival of cancer cells in culture, but did not pan out in clinical application; combined, they may be able to overcome the cancer's natural robustness. Paired with the chemotherapeutic agents, irinotecan and temozolomide, the new combo successfully increased survival time in mice and reduced tumor growth by slowing cell division and spurring apoptosis. These results suggest RIST may be a promising treatment for brain tumors.

What's new?

A common mechanism for acquired resistance to cancer chemotherapy is upregulation of the ABCB1 pump. This study shows that the proliferation of multidrug-resistant ABCB1-expressing cells is decreased significantly with the administration of relatively nontoxic chemotherapy drug substitutes, or ersatzdroges, that serve as pump substrates. In vivo 18-FDG-PET imaging revealed increased glucose uptake by tumors in mice following systemic ersatzdroge administration. The findings suggest that ersatzdroges, by increasing the energy expenditure of resistant cells, expose resistant cell populations and reduce their fitness and ability to proliferate. Since many ersatzdroges are currently available (e.g., Verapamil), the strategy could be applied clinically.

What's new?

A relatively little known myokine, irisin, might be a missing link between exercise and its protective effect on breast cancer. Researchers from the University of New Mexico treated several breast cancer cell lines with the myokine and observed decreased viability, proliferation and migration. These findings were linked to proapoptotic and anti-inflammatory effects involving the transcription factor NF-κB. The authors point to potential therapeutic benefits as irisin did not affect growth or survival of non-malignant cells and synergized with doxorubicin, currently widely used in breast cancer chemotherapy.