What's new?

While there is evidence that Mantle Cell Lymphoma (MCL) cells rely on B-cell receptor (BCR)-mediated signalling pathways for their survival, the nature of such activation remains unknown. Significant progress in MCL treatment was nonetheless achieved through therapies targeting BCR-associated kinases such as Ibrutinib and Fostamatinib. Here, the authors showed that the inhibition of SYK by Fostamatinib or BTK by Ibrutinib altered BCR-induced secretion of IL1β, IL6, IL8, VEGFα, TNFα, and CCL5. These effectors could mediate survival of MCL cells through their homing and adhesion to bone marrow stromal cells. Moreover, Fostamatinib and Ibrutinib impaired NF-κB-dependent STAT3 activation, leading to apoptosis.

What's new?

Patients with head and neck squamous cell cancers often develop resistance to radiotherapy. To figure out how, these authors investigated AKT phosphorylation in the tumor cells. AKT kinase boosts cell proliferation when it is activated by phosphorylation at two possible sites. Could the location of phosphorylation predict whether the tumor will develop resistance? These results suggest it could. The authors show that patients with more phosphorylation at serine 473 had worse survival; furthermore, they showed that reducing phosphorylation at this site increased cancer cells' vulnerability to irradiation. Phosphorylation at the other site, threonine 308, did not affect survival.

What's new?

The Wnt signaling pathway plays a role in many cancers. The central player in this pathway is beta-catenin; when this protein is knocked out, tumors wither and cancer stem cells disappear. In this study, the authors found beta-catenin hanging out in the stromal fibroblasts of a quarter of skin carcinomas. The authors further showed that an active Wnt pathway in the fibroblasts would turn on various growth-promoting elements, including chemokines IL-8 and CCL-2, and matrix-degrading metalloproteinases. These results suggest that activation of the Wnt pathway in the tumor microenvironment helps spur the growth and spread of skin cancer.

What's new?

Mutations and alterations in the expression and activity of CK1 isoforms--which play important roles in many cellular processes--are known to contribute to tumorigenesis and tumor progression. The authors show that expression of CK1ɛ correlates with the survival of colorectal cancer patients. Furthermore, they identify CK1δ mutations leading to altered kinetic parameters in vitro and, when introduced into a carcinoma cell line, altered tumor growth in vivo. Since the mutant with high oncogenic potential also displays greater sensitivity to CK1-specific inhibitors, the findings underline the potential use of CK1-specific inhibitors in the treatment of colorectal cancer and personalized medicine.

What's new?

Colorectal cancers (CRC) with microsatellite instability (MSI) display unique clinicopathological features including a mucinous pattern with frequent expression of MUC2 and MUC5AC. The mechanisms underlying such altered pattern of expression, however, remain unclear. This is the first study investigating the methylation profile of mucin genes in different CRC subgroups. It shows that MUC2 and MUC5AC expression in CRC is partially regulated by DNA methylation, and that such MUC5AC regulation is specific for MSI tumors. MUC5AC hypomethylation is a strong predictor of MSI in CRC independently of other clinicopathological characteristics and may serve as a specific marker of the serrated pathway.

What's New?

Infection with Kaposi sarcoma associated-herpesvirus (KSHV) and HIV, the major risk factor for Kaposi sarcoma, is common in sub-Saharan Africa. However, little is known about the evolution of KSHV antibody responses in HIV-infected individuals prior to the clinical onset of KS. This study shows that antibody titres against KSHV antigens K8.1 and latency-associated nuclear antigen (LANA) increase significantly in the six years leading up to HIV-associated KS. Titres of K8.1, a lytic antigen, rose more than LANA titres, indicating that the activation of genes in the lytic cycle of viral replication is important in KS development.

What's new?

Cutaneous human papillomavirus (HPV) infection may act in concert with UV radiation exposure to fuel the early progression of non-melanoma skin cancer. The molecular mechanism underlying that interaction has been elusive but may involve the E3 ubiquitin ligase HERC1, according to the present study. HERC1 was discovered to associate with the E6 protein of cutaneous HPV5. E6 prevents UV-induced apoptosis by signaling for degradation of the pro-apoptotic protein BAK. The authors show that E6 targets only activated BAK for proteolysis and requires HERC1 to carry out degradation signaling.

What's new?

In spite of the advances of targeted therapies, conventional chemotherapy with DTIC or TMZ is likely to remain useful for stage IV melanoma patients who are mutation-negative or develop drug resistance. Predictive biomarkers to identify the minority of patients who benefit from DTIC/TMZ treatment are however lacking. This study reports that MGMT promoter methylation in melanoma metastases results in MGMT gene silencing. MGMT promoter methylation is associated with significantly improved response rate to DTIC/TMZ single agent therapy and longer progression-free survival in stage IV melanoma patients, suggesting its potential use as a biomarker in melanoma, as already seen in glioblastoma.

What's new?

Concurrent testing (co-testing) for cytology and human papillomavirus (HPV) has been recommended for primary cervical-cancer screening since 2002. In this study, the authors found that, although co-testing more than tripled between 2007 and 2012, it still occurs in fewer than 20% of women. On the other hand, 82% of women with ASC-US cytology were then tested for HPV. The registry used in this study (the New Mexico HPV Pap Registry) provides a model for evaluating cervical screening and follow-up outcomes and potentially the model can be translated to other cancers.

What's new?

The development of new non-invasive tests (NITs) for colorectal cancer (CRC) screening has centered primarily on improving the detection of invasive disease. But according to this study, whether new NITs are viable alternatives to immunochemical fecal occult blood tests—already established screening tests for CRC–depends also on their ability to detect adenomas, the precursor lesions of CRC. Without that ability, immunochemical fecal occult blood tests retain their superiority over newer NITs, many of which attempt to detect biomarkers in stool or blood. The identification of adenoma-specific markers could be critical to the advance of NITs for CRC screening.

What's new?

High cancer mortality in Africa is associated with an array of factors, including deficiencies in public education and health resources, which are likely to persist for decades to come. In the interest of effecting cancer control quickly and by economically practicable means, the authors of the present investigation in Tanzania compared routine self-referral against proactive visitation by health aides trained in the identification of suspected lesions. Significant improvement toward earlier cancer diagnosis was observed in the village where proactive visitation was implemented. Proactive referral could significantly improve the effectiveness of therapy, leading to reductions in cancer mortality in Africa.

What's new?

It's tricky to study the relationship between weight gain and colorectal cancer, and previous studies have returned conflicting results. This meta-analysis collated data from 8 studies in search of a clear indication of the effect of adult weight gain on CRC risk. Unlike body mass index, which includes both fat and muscle mass, adult weight gain can reveal changes in metabolic efficiency with age that make one vulnerable to cancer. These authors found that only in men, weight gain does appear to increase risk of colorectal cancer.

What's new?

Vitamin D is known to affect immune function and suppress inflammation. In this study, the authors found that lower vitamin D levels at diagnosis and a history of smoking are both associated with a higher incidence of ulceration of primary melanoma, as well as with decreased survival. While a causal link hasn't yet been proven, the authors conclude that it would be prudent to suggest that melanoma patients should stop smoking, and that vitamin D depletion should be avoided.

What's new?

Cutaneous melanomas are caused by sunlight, but the patterns of sun exposure that lead to disease appear to vary according to host factors and the anatomic location of the melanocytes involved. Using a case-case approach, the authors of the present study explored the predictors of chronic sun damage in skin adjacent to melanomas arising on the trunk (a sun-protected site). They found that such melanomas are associated with sun-sensitive phenotype, history of sunburns, measures of cumulative sun exposure, and numbers of actinic keratoses.

What's new?

Acrylamide is formed in a variety of foods, and some evidence suggests it may cause cancer. How dangerous is dietary acrylamide? This study collated data from 32 earlier projects evaluating the relationship between acrylamide consumed in foods and cancer risk. Of fourteen cancer sites represented, only kidney cancer showed a possible increase in risk associated with dietary acrylamide. When they narrowed the analysis to people who had never smoked, dietary acrylamide appeared to slightly increase risk of endometrial and ovarian cancer as well.

What's new?

Diets rich in carbohydrate trigger increases in blood glucose and insulin levels, events that may be involved in the etiology of colorectal cancer. But carbohydrates vary in their impact on blood glucose levels, reflected in their glycemic index (GI) values, and whether high GI carbohydrates raise cancer risk remains much debated. Here, high dietary GI and elevated intake of carbohydrates from high GI foods were associated with increased risk of colorectal cancer. A diet rich in low GI carbohydrates, by contrast, was associated with a reduced risk of disease.

What's new?

Vitamin B6 status is reflected in the measure of its active form, pyridoxal 5'-phosphate (PLP). Studies disagree, however, as to whether or not PLP measures are meaningful in relation to cancer risk, which has necessitated a search for additional markers of vitamin B6 status. In this study, inflammation-related changes in vitamin B6 catabolism were captured effectively by a novel marker, the 4-pyridoxic acid (PA) /(pyridoxal (PL) + PLP) ratio (PAr). Analyses based on the detection of PAr suggest that increased vitamin B6 metabolism and disposal are linked to increased cancer risk, particularly for lung cancer.

What's new?

Preclinical drug evaluation in head and neck squamous cell carcinoma (HNSCC) is challenged by the inability of established cell lines to predict clinical impact. It may be possible to overcome that problem with patient-derived xenografts (PDX), which more closely reflect tumor characteristics. Here, a large collection of PDXs were established for HNSCC and tested for therapeutic response. The mTOR inhibitor everolimus was found to be active in a majority of the models. Biomarkers capable of predicting tumor response to everolimus were not identified, though increased expression of RPS6KB1, a member of the mTOR pathway, was common among responders.

What's new?

So few women are diagnosed with small cell carcinoma of the uterine cervix (SCCC) that a clear approach to SCCC treatment has yet to be established. A key part of that approach could be radiation therapy, though tumor sensitivity to radiation varies significantly among patients. Here, radiation sensitivity was explored in SCCC cells isolated from six patients via the cancer tissue–originated spheroid (CTOS) method. Irradiation experiments showed variations in radiation sensitivity, both in vitro and in vivo. Elevated levels of HIF-1α were detected in radio-resistant CTOSs within hours of irradiation. With HIF-1α suppression, radiation sensitivity was restored.

What's new?

Some patients have benefitted from drugs that inhibit IGF-1 receptor (IGF-1R), but there was no way to predict in advance which patients will respond. This study shows that if molecules involved in homologous recombination (HR)–such as RAD51, BRCA2, or CDK1–are blocked, cells become more sensitive to IGF-1R inhibition. Given previous work showing that IGF-1R inhibition partially suppresses HR, these data suggest that IGF-1R-inhibited cells are more dependent on residual HR to repair endogenous DNA damage, and HR-deficient tumors may be sensitive to IGF-1R inhibitory drugs.

What's new?

Ingestion of aristolochic acid (AA) causes severe nephropathies and carcinomas of the upper urinary tract, and represents a significant public health problem with millions of people at risk worldwide. In this study of renal disease patients in an endemic region, the authors identified a previously unrecognized type of renal cell carcinoma that harbors the mutational signature of this potent carcinogen. Their findings suggest that the putative causal role of AA in renal cortex carcinogenesis should be broadly addressed in high-risk regions marked by inadvertent exposure to AA or widespread use of AA-containing herbal remedies.

What's new?

The transformation to intestinal metaplasia (IM) is a critical step toward gastric adenocarcinoma, potentially marking the point of no return, wherein IM tissue cannot be coaxed back to its original state. While well-defined morphologically and clinically, however, the functional significance of that transformation remains uncertain. Here, detailed analysis of microsatellite markers of IM tissue from gastric cancer patients indicates that genomic alterations are prevalent and highly variable in metaplastic tissues. Hence, despite sharing traits with intestinal glands, IM tissues are functionally distinct and may provide the random and accelerated mutation background that is necessary for malignant progression.