Trends in cancer research最新文献

The association between vitamin D and cancer has long been studied, but the results have been variable. Thus, there does not seem to be a consensus on whether vitamin D has a beneficial anti-cancer effect. This review not only summarizes the association between vitamin D and cancer risk and results of clinical trials involving vitamin D, but explores some of the reasons that contribute to the variability of study outcomes. Highlighted are single nucleotide polymorphisms (SNPs) that contribute to variability in the efficacy of vitamin D supplementation. Understanding these differences can personalize approaches to optimize the effectiveness of vitamin D in limiting cancer risk.

Tumor suppressor function of Annexin-A7 (ANXA7) was demonstrated by cancer-prone phenotype in Anxa7(+/-) mice and ANXA7 profiling in human cancers including prostate and breast. Consistent with its more evident in vivo tumor suppressor role in prostate cancer, wild-type(wt)-ANXA7 in vitro induced similar G2-arrests, but reduced survival more drastically in prostate cancer cells compared to breast cancer cells (DU145 versus MDA-MB-231 and -435). In all three hormone-resistant cancer cell lines, wt-ANXA7 abolished the expression of the oncogenic low-molecular weight (LMW) cyclin E which was for the first time encountered in prostate cancer cells. Dominant-negative nMMM-ANXA7 (which lacks phosphatidylserine liposome aggregation properties) failed to abrogate LMW-cyclin E and simultaneously induced fibroblast growth factor 8 (FGF8) in DU145 that was consistent with the continuing cell cycle progression and reduced cell death. Adenoviral vector alone induced FGF8 in MDA-MB-231/435 cell lines, but not in DU145 cells. Our data indicated that the LMW-Cyclin E expressions in breast cancer and prostate cancer cell-lines were differentially regulated by wild-type and dominant-negative ANXA7 isoforms, demonstrating a different survival mechanism utilized by breast cancer cells. Conventional tumor suppressor p53 failed to completely abolish FGF8 and LMW-cyclin E in breast cancer cells, which were eventually translated into their survival. Thus, ANXA7 tumor suppression could modulate FGF8 and cyclin E expression, and control implying more specific associations with the annexin properties of ANXA7 in prostate tumorigenesis.

Colorectal cancer (CRC) is a major health challenge worldwide. Factors thought to be important in CRC etiology include diet, microbiome, exercise, obesity, a history of colon inflammation and family history. Interventions, including the use of non-steroidal anti-Inflammatory drugs (NSAIDs) and anti-inflammatory agents, have been shown to decrease incidence in some settings. However, our current understanding of the mechanistic details that drive CRC are insufficient to sort out the complex and interacting factors responsible for cancer-initiating events. It has been known for some time that the development of CRC involves mutations in key genes such as p53 and APC, and the sequence in which these mutations occur can determine tumor presentation. Observed recurrent mutations are dominated by C to T transitions at CpG sites, implicating the deamination of 5-methylcytosine (5mC) as a key initiating event in cancer-driving mutations. While it has been widely assumed that inflammation-mediated oxidation drives mutations in CRC, oxidative damage to DNA induces primarily G to T transversions, not C to T transitions. In this review, we discuss this unresolved conundrum, and specifically, we elucidate how the known nucleotide excision repair (NER) and base excision repair (BER) pathways, which are partially redundant and potentially competing, might provide a critical link between oxidative DNA damage and C to T mutations. Studies using recently developed next-generation DNA sequencing technologies have revealed the genetic heterogeneity in human tissues including tumors, as well as the presence of DNA damage. The capacity to follow DNA damage, repair and mutagenesis in human tissues using these emerging technologies could provide a mechanistic basis for understanding the role of oxidative damage in CRC tumor initiation. The application of these technologies could identify mechanism-based biomarkers useful in earlier diagnosis and aid in the development of cancer prevention strategies.

There have been six epigenome-wide association studies (EWAS) for breast cancer risk using blood DNA from prospective cohorts published thus far, and the only consistent finding is a global loss of methylation observed in breast cancer cases compared with controls, with no individual CpG sites passing validation across studies. In contrast, a more successful approach has been the identification of EWAS signatures of cancer risk factors such as smoking, body mass index, age and alcohol use with numerous validated CpG sites. These signatures may be used as a molecular test to quantify cancer risk associated with these factors. It is clear from the larger EWAS of risk exposures that similar-sized large collaborative studies may be needed to robustly identify DNA methylation signatures of breast cancer risk.

We have previously identified a single-item measure for baseline overall quality of life (QOL) as a strong prognostic factor for survival, and that fatigue was an important component of patient QOL. To explore whether patient-reported fatigue was supplemental or redundant to the prognostic information of overall QOL, we performed a patient-level pooled analysis of 43 North Central Cancer Treatment Group (NCCTG) and Mayo Clinic Cancer Center (MCCC) oncology clinical trials assessing the effect of baseline fatigue on overall survival (OS). 3,915 patients participating in 43 trials provided data at baseline for fatigue on a single-item 0-100 point scale. OS was tested for association with clinically deficient fatigue (CDF, score 0-50, n = 1,497) versus not clinically deficient fatigue (nCDF, score 51-100, n = 2,418). We explored whether fatigue contributed to overall survival in the presence of performance status and overall QOL. We used Cox proportional hazards models that adjusted for the effects of overall QOL, performance score, race, disease site, age and gender. Baseline fatigue was a strong predictor of OS for the entire patient cohort (CDF vs. nCDF: 31.5 months vs > 83.9 months, p < 0.0001). The effect sizes of fatigue on survival were more variable across different disease sites than was seen for overall QOL (GI, esophageal, head and neck, prostate, lung, breast and others). After controlling for covariates, including performance status and overall QOL, baseline fatigue remained a strong prognostic factor in multivariate models (CDF vs. nCDF: HR = 1.23, p = 0.02). Baseline fatigue is a strong and independent prognostic factor for OS over and above performance status (PS) and overall QOL in a wide variety of oncology patient populations. Single-item measures of overall QOL and fatigue can help to identify vulnerable subpopulations among cancer patients. We recommend these single-item measures for routine inclusion as a stratification factor or key covariate in the design and analysis of oncology treatment trials.

Metastasis is a multi-step process that ultimately depends on the ability of disseminating cancer cells to establish favorable communications with their microenvironment. The tumor microenvironment consists of multiple and continuously changing cellular and molecular components. One of the factors regulating the tumor microenvironment is TNF-α, a pleiotropic cytokine that plays key roles in apoptosis, angiogenesis, inflammation and immunity. TNF-α can have both pro- and anti-tumoral effects and these are transmitted via two major receptors, the 55 kDa TNFR1 and the 75 kDa TNFR2 that have distinct, as well as overlapping functions. TNFR1 is ubiquitously expressed while the expression of TNFR2 is more restricted, mainly to immune cells. While TNFR1 can transmit pro-apoptotic or pro-survival signals through a complex network of downstream mediators, the role of TNFR2 is less well understood. One of its main functions is to act as a survival factor and moderate the pro-apoptotic effects of TNFR1, particularly in immune cells. In this review, we summarize the evidence for the involvement of the TNF system in the progression of the metastatic process from its contribution to the early steps of tumor cell invasion to its role in the colonization of distant sites, particularly the liver. We show how the TNF receptors each contribute to these processes by regulating and shaping the tumor microenvironment. Current evidence and concepts on the potential use of TNF targeting agents for cancer prevention and therapy are discussed.

The relationship between cancer progression and chronic inflammation is well documented but poorly understood. The innate immune system has long been recognized as the first line of defense against invading pathogens. More recently, endogenous molecules released from tissue matrix (Damage Associated Molecular Patterns [DAMPs]) following tissue injury or periods of active matrix remodeling have also been identified as regulators of innate immunity. DAMPs have been identified as ligands for Toll-like receptors (TLRs), a family of cell-surface proteins which regulate the immune response. TLRs have been identified on resident tissue cells as well as most tumor cells. Therefore, dysregulation of the innate immune response secondary to biochemical and mechanical driven changes in the extracellular matrix of the tumor microenvironment may be a critical component of the chronic inflammation associated with tumor progression. Here we review the role of extracellular matrix (ECM)-derived DAMPS in the activation of TLR4 signaling in the context of tumor progression. We also explore the various types of topographical changes that can lead to ECM-derived DAMPs and their contribution to TLR4 activation.

Cell junctions are sites of intercellular adhesion that maintain the integrity of epithelial tissue and regulate signalling between cells. These adhesive junctions are comprised of protein complexes that serve to establish an intercellular cytoskeletal network for anchoring cells, in addition to regulating cell polarity, molecular transport and communication. The expression of cell adhesion molecules is tightly controlled and their downregulation is essential for epithelial-mesenchymal transition (EMT), a process that facilitates the generation of morphologically and functionally diverse cell types during embryogenesis. The characteristics of EMT are a loss of cell adhesion and increased cellular mobility. Hence, in addition to its normal role in development, dysregulated EMT has been linked to cancer progression and metastasis, the process whereby primary tumors migrate to invasive secondary sites in the body. This paper will review the current understanding of cell junctions and their role in cancer, with reference to the abnormal regulation of junction protein genes. The potential use of cell junction molecules as diagnostic and prognostic markers will also be discussed, as well as possible therapies for adhesive dysregulation.