International Journal of Cancer

What's new?

While alterations in micro-RNA (miRNA) expression have been implicated in the pathogenesis of human malignancies, they have not been investigated extensively in pre-malignant cells. Here, re-expression of the miRNAs miR-182 and miR-203 in mesenchymal non-transformed prostate cancer (EPT1) cells was found to induce mesenchymal to epithelial transition (MET) features and self-sufficiency of growth signals. The acquisition of the oncogenic characteristics was mediated through repression of SNAI2, which was demonstrated to be a common target of miR-182 and miR-203. The dual functions of these molecules shed light on their complex mechanisms in tumor progression.

What's new?

Pituitary homeobox-2 (PITX2) is an essential transcription factor in embryonic development. While PITX2 is overexpressed in some cancers, its importance in tumorigenesis remains unclear. Here the authors investigate the role of PITX2 in regulating the expression of ABCB1, a P-glycoprotein that plays a major role in the multidrug resistance of malignant cells. Using human renal cancer cell lines, they show for the first time that cell survival in the presence of doxorubicin is caused by up-regulation of ABCB1 as a downstream target of PITX2, in a β-catenin-independent mechanism. PITX2 is a putative target for cancer therapy in drug-resistant renal carcinoma.

What's new?

Intercellular adhesion molecule-1 (ICAM-1) appears to play an important role in several malignancies. Increased ICAM-1 expression may correlate with more favorable prognosis in some cancers, perhaps by enhancing immune surveillance. However, ICAM-1 may also promote tumor growth. In this study, the authors found that oral cancer cells express ICAM-1 at the invasive frontal region, and that cancer cell-derived ICAM-1 plays a role in angiogenesis, tumor invasion, and lymph node metastasis. They also found that ICAM-1 acts as a macrophage/cancer-cell adhesion molecule. These findings indicate that ICAM-1 plays an important role in oral cancer progression.

What's new?

Hedgehog (Hh) signaling plays an important role in maintaining leukemic stem cells. As a result, its dysregulation has been implicated in various malignancies. While certain aspects of Hh regulation remain obscure, it appears to be mediated in part by the transducer protein Smoothened (Smo), the upregulation of which was discovered in this study to be associated with reduced expression of microRNA-326 (miR-326) in CD34⁺ cells from patients with chronic myelogenous leukemia (CML). The findings could contribute to a better understanding of the molecular mechanisms underlying Hh signaling and its involvement in the pathophysiology of CML.

What's new?

Mutation of the BRAF proto-oncogene contributes to the development of certain types of cancer, though the significance of its splice variants, which have been described in human cells, remains unclear. Here, four new BRAF splice variants leading to carboxy-terminal truncation of the B-Raf protein were identified in colorectal cancer cells. Truncated B-Raf isoforms had total loss of kinase activity, suggesting a decreased sensitivity to growth signals. Identifying ways to increase the amount of kinase-dead B-Raf in tumor cells could lead to new treatments for BRAF-mutated cancers.

What's new?

The recent classification of Merkel cell polyomavirus (MCV) infection as probably carcinogenic and of BK virus (BKV) and JC virus (JCV) infections as possibly carcinogenic suggests that these agents may play a role in the development of certain malignancies. In this evaluation, which focused on bladder cancer specifically, disease was found to be associated with high seroreactivity for BKV and MCV but not JCV. There was no association of seroreactivity with disease stage or grade. The results suggest that urothelial cell carcinoma, the most common type of bladder cancer in industrialized countries, may have an infectious etiology.

What's new?

An estimated one in five cancer cases worldwide are caused by infection, with the majority being caused by tumor viruses. The present study aimed to establish an association between human polyomavirus infection and non-small cell lung cancer (NSCLC). The data implicate Merkel cell polyomavirus (MCPyV) in 9.1% of the cases in a cohort of 110 NSCLC patients. The expression profile of genes involved in oncogenesis also point to the deregulation of BRAF and Bcl-2 in MCPyV-positive NSCLC cells. These findings suggest the involvement of MCPyV in non-small cell lung cancer through deregulation of BRAF and Bcl-2.

What's new?

Malignant mesothelioma (MM) is an aggressive cancer with poor prognosis. However, some patients demonstrate improved survival in association with an anti-tumor immune response, suggesting that immunotherapy may be a useful treatment strategy for the disease. In this study, a novel vaccine based on Fowlpox vector expression of the inhibitory apoptotic protein survivin was found to successfully trigger an immune response in an MM mouse model. The response resulted in delayed tumor growth and improved survival, indicating that the vaccine could serve as the basis for the development of clinically relevant MM immune-based treatments.

What's new?

Some chemotherapies not only kill cancer cells, but also enhance immune responses against those cells. In this study, the authors found that when tumor cells were exposed to nonlethal doses of docetaxel, they became more sensitive to killing by cytotoxic T lymphocytes. This process appears to be mediated by a number of molecules, including calreticulin. Even tumor cells that were resistant to docetaxel became more susceptible to lysis by CTLs. These results suggest that chemotherapy combined with immunotherapy might improve outcomes in patients who have failed chemotherapy alone.

What's new?

The human papillomavirus (HPV) genome is subject to changes in DNA methylation. Here, the quantification of DNA methylation in HPV16 from exfoliated cervical cells of women with detectable virus was found to be significantly associated with cervical intraepithelial neoplasia grade 2 or 3. The methlyation score was based on the combined mean of methylation specifically in the HPV16 late regions (L1 and L2). The approach could be used to aid decisions concerning triage to colposcopy and has the potential to be expanded to other carcinogenic HPVs.

What's new?

Short bits of regulatory RNA called miRNAs circulate in the blood, and they sometimes prove useful for diagnosing cancers. This study investigated whether miRNAs could help distinguish between benign and cancer-related fluid build-up in the lungs. One miRNA, miR-198, was expressed much less in samples from patients with the pre-cancerous condition than those whose fluid accumulation was benign. When they quantified miR-198's predictive ability, the authors found that it performed as well or better than two common cancer markers, CEA and CYFRA. The newly identified miRNA, therefore, could be quite handy for diagnosing lung adenocarcinomas.

What's new?

Radiographic screening is currently the main method for gastric cancer screening in Japan, but endoscopy is expected to become widely adopted due to its high detection rate. This study compares the sensitivity of radiographic and endoscopic screening using the incidence method based on the results of community-based screenings in Japan. The findings suggest that endoscopic screening for gastric cancer had a higher sensitivity than radiographic screening in both the screenings. However, further study is needed to evaluate mortality reduction and investigate the magnitude of overdiagnosis in endoscopic screening for gastric cancer.

What's new?

Inactivation of miRNAs by methylation occurs in various cancers, but little is known so far about methylation of miRNAs in liver cancer. In this study, the authors compared the methylation status of 13 differentially methylated miRNAs in primary hepatocellular carcinoma, benign liver tumors, and normal liver specimens. They found epigenetic inactivation by methylation in most of the cancer cell lines. This hypermethylation could be used to distinguish between cancerous and benign liver tumors.

What's new?

The cell-surface protein Metadherin (MTDH) is involved in tumorigenesis and progression in many malignancies. In this study, the authors found that MTDH overexpression correlated with more aggressive tumors and poor prognosis in patients with laryngeal squamous cell carcinoma (LSCC). Expression levels of MTDH may thus provide a useful new prognostic biomarker for metastasis and recurrence, and may aid in the planning of treatment strategies following tumor resection.

What's new?

Studies on Western populations have reported that increased calcium intake can help prevent breast cancer. Asian populations, however, have low incidence of breast cancer, yet consume little calcium. This study investigated whether any link can be observed between calcium intake and breast cancer in Asian populations. The authors found no association between breast cancer risk and calcium, consumed either from food or supplements, in a Singaporean Chinese population. This is in contrast to three previous studies on Asian populations in Japan and China, but this could be attributed to differences in study design; while the others were retrospective studies, the current paper reports the first prospective study to investigate this question.

What's new?

Mortality from Hodgkin's lymphoma differs between developed and less-developed regions of the world, with mortality rates having declined markedly in the former but less so in the latter. In this study of Hodgkin's lymphoma mortality in 12 Latin American countries, selected based on population size and completeness of mortality data, appreciable declines were registered for the period 1997–2008 in most of the countries assessed, with rates reaching those observed in North America. However, substantial excesses remained in Cuba, Mexico, and Venezuela, calling for urgent intervention in these middle-income countries.

What's new?

Genetic variations in the nucleotide excision repair (NER) pathway may underlie interindividual differences in DNA repair capacity and thereby influence cancer risk and prognosis as well as susceptibility to genotoxicity associated with cancer therapy. This investigation lends support to that idea, revealing that variations in core NER genes may exert significant influence over disease-free survival and risk of disease recurrence in radiation-treated squamous cell carcinoma of the oropharynx (SCCOP) patients. The variants, which included XPC-rs2228000, XPD-rs1799793, and XPG-rs17655, may collectively serve as a marker of susceptibility to SCCOP recurrence, particularly in SCCOP patients who test positive for human papillomavirus.

What's new?

Widespread screening for breast cancer means that more cancers are diagnosed than would be without the screening. Some of these cancers, however, would never have harmed the patient if left undetected. This overdiagnosis is difficult to measure, and in the current paper, the authors studied a cohort of women over a period of 10 years after they participated in cancer screening. They found an excess incidence of breast cancer during the initial screening period, followed by a deficit that lasted a decade after the women left the program. From this data, the authors estimated the proportion of overdiagnosis among women who participated in the screening program versus those who had not attended the screenings.

What's new?

Studies have suggested that musculoskeletal pain may be linked to cancer, though whether pain is an early symptom or a cause of cancer has remained unclear. In this study, new back, hip, and neck problems were found to be associated with the later diagnosis of prostate, breast, and lung cancer, mostly in the first year after baseline musculoskeletal consultation. However, risk of cancer is low and the association may be explained by liability of bony metastases from primary cancer sites, with pain being an early marker for disease.

What's new?

As in much of Africa, marked lifestyle changes have been observed in Zimbabwe since the latter part of the 20th century. During that time, Zimbabwe was also severely affected by HIV/AIDS. According to this study, these factors were coincident with changes in cancer risk and incidence in the black population of Harare, Zimbabwe. The findings reveal increased incidence for certain cancers typically associated with the Westernization of lifestyle, including cancers of the breast and prostate, as well as a rise and fall in incidence of Kaposi sarcoma, a pattern that mirrors the peak and subsequent wane of the HIV/AIDS epidemic.

What's new?

Recent evidence suggests that some ovarian cancers arise from the ovary while others originate in the fallopian tube, but whether risk factors vary by site of origin is unknown. Here the authors classified ovarian cancer using tumor measurements as a proxy for cell of origin, evaluating risk factors by tumor dominance for the first time. They found that risk factors for tumors arising from ovarian versus fallopian tube sites may differ, with reproductive factors being more important for ovarian-derived tumors. Understanding risk factor profiles for potentially independent carcinogenic pathways is needed to better understand the etiology of ovarian cancer.

What's new?

The relationship between body fat and cancer risk has been well studied, usually focusing on body-mass index (BMI). However, the relationship may not be that simple. In this study, the authors found that height and waist circumference correlated with cancer risk, but if these factors were adjusted for, BMI did not. Height was associated with increased risk regardless of menopausal status. Waist circumference was associated with decreased risk before menopause, but this changed to an increased risk after menopause. The authors conclude that height and waist circumference play significant and independent roles in cancer risk.

What's new?

Resistance to temozolomide is a significant obstacle in the treatment of glioblastoma and has necessitated a search for alternative therapeutic approaches. One such approach may entail combination therapy with the integrin inhibitor cilengitide and the camptothecin derivative belotecan, as described in this report. Together, the agents demonstrated enhanced cytotoxic effects and caused increased apoptosis in glioblastoma cells, while in vivo they led to a reduction in tumor volume and an increase in survival. The effects might be attributed to angiogenesis inhibition by cilengitide as well as to apoptotic cell death induced by both drugs.

What's new?

Many antibody-cytokine fusion proteins known as immunocytokines (ICKs) have been developed to deliver cytokines with antitumoral potencies to the tumor microenvironment using antibodies directed against a tumor-associated antigen. Several ICKs using notably interleukin 2 (IL2) present encouraging results in phase-II clinical trials. IL15, which belongs to the IL2 family, and the superagonist RLI, which the authors previously developed, present many advantages over IL2 as immunological adjuvant, such as chemotherapy potentiation and toxicity reduction. Here they show that a RLI-based ICK targeting the GD2 tumor antigen has a higher therapeutic potency in vivo than RLI and antiGD2 alone or in combination.

What's new?

Interleukin-21 (IL-21) has shown promise as a therapy for several types of cancer, and has been found to induce apoptosis in diffuse large B-cell lymphoma (DLBCL) cell lines. In this study, however, the authors found that IL-21 induces proliferation rather than apoptosis of the “Farage” DLBCL cell line, which carries Epstein-Barr virus (EBV). When the EBV genes were downregulated in these cells, IL-21 no longer induced proliferation, and apoptosis increased. These findings reveal a previously unknown role of EBV in DLBCL that may be relevant to current studies using IL-21 as a therapy.

What's new?

Human plasmacytoid dendritic (pDC) cells are known to infiltrate tumors but are functionally impaired, and their infiltration is associated with poor prognosis for tumor patients. The present study uncovers cooperation between TGF-beta and TNF-alpha as a major in vivo mechanism blocking type I interferon production by tumor-associated pDCs through inhibition of IRF7 signaling. The authors propose that a combination of TGF-beta/TGF-beta receptor antagonists with TLR7/9 agonists may restore tumor-associated pDCs' innate immune functions thus restoring a more effective anti-tumor immunity and leading to innovative new treatments for tumors such as breast cancer.