Western populations are becoming increasingly sedentary and the incidence of nonalcoholic fatty liver disease (NAFLD) is increasing and becoming one of the most common causes of liver disease ...worldwide. Also, NAFLD is considered one the new emerging risk factors for development of tumors of the gastro-intestinal tract, particularly hepatocellular carcinoma (HCC). Visceral obesity is an important risk factor for the onset of NAFLD. An accumulation of ectopic fat, including visceral obesity and fatty liver leads to a dysfunction of the adipose tissue with impaired production of adipocytokines which, in turn, favor an increase in pro-inflammatory cytokines. In this review, we discuss how the obesity-related chronic state of low-grade inflammation and the presence of NAFLD lead to the emergence of a microenvironment favorable to the development of cancer.
Epidemiological and clinical studies support the association between nutrition and development or progression of different malignancies such as colon, breast, and prostate cancer, defining these ...tumors as diet-associated cancer. The Mediterranean diet shows inverse associations with metabolic diseases, cardiovascular pathologies and various types of cancer. Many bioactive nutrients of the Mediterranean diet have been identified as factors protective against these types of pathologies. The epigenome has been identified as the primary goal of modulations in gene expression related to these molecular nutrients. In fact, they can modify the epigenome and can be incorporated into the 'epigenetic diet', which translates into a diet regimen that can be used therapeutically for health or preventative purposes. Most epigenetic changes are influenced by lifestyle and nutrition. Epigenetic therapy is a new area for the development of nutraceuticals whose absence of toxicity can represent a valid asset in cancer prevention strategies. Recent advances in understanding the mechanisms of nutrigenomics, nutrigenetics and nutraceuticals have led to the identification of superfoods capable of favorably conditioning gene expression. In this review, we highlight the importance of nutraceuticals present in the Mediterranean diet as epigenetic modifiers both in the mechanisms of tumor onset and as protective agents.
The immunotherapy with immune checkpoints inhibitors (ICI) has changed the life expectancy in metastatic melanoma (MM) patients. Nevertheless, several patients do not respond hence, the ...identification and validation of novel biomarkers of response to ICI is of crucial importance. Circulating extracellular vesicles (EVs) such as PD-L1
EV mediate resistance to anti-PD1, instead the role of PD1
EV is not fully understood.
We isolated the circulating EVs from the plasma of an observational cohort study of 71 metastatic melanoma patients and correlated the amount of PD-L1
EVs and PD1
EVs with the response to ICI. The analysis was performed according to the origin of EVs from the tumor and the immune cells. Subsequently, we analysed the data in a validation cohort of 22 MM patients to assess the reliability of identified EV-based biomarkers. Additionally we assessed the involvement of PD1
EVs in the seizure of nivolumab and in the perturbation of immune cells-mediated killing of melanoma spheroids.
The level of PD-L1
EVs released from melanoma and CD8
T cells and that of PD1
EVs irrespective of the cellular origin were higher in non-responders. The Kaplan-Meier curves indicated that higher levels of PD1+ EVs were significantly correlated with poorer progression-free survival (PFS) and overall survival (OS). Significant correlations were found for PD-L1
EVs only when released from melanoma and T cells. The multivariate analysis showed that high level of PD1
EVs, from T cells and B cells, and high level of PD-L1
EVs from melanoma cells, are independent biomarkers of response. The reliability of PD-L1
EVs from melanoma and PD1
EVs from T cells in predicting PFS was confirmed in the validation cohort through the univariate Cox-hazard regression analysis. Moreover we discovered that the circulating EVs captured nivolumab and reduced the T cells trafficking and tumor spheroids killing.
Our study identified circulating PD1
EVs as driver of resistance to anti-PD1, and highlighted that the analysis of single EV population by liquid biopsy is a promising tool to stratify MM patients for immunotherapy.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MicroRNAs (miRNAs, or miRs) are single-strand short non-coding RNAs with a pivotal role in the regulation of physiological- or disease-associated cellular processes. They bind to target miRs ...modulating gene expression at post-transcriptional levels. Here, we present an overview of miRs deregulation in the pathogenesis of multiple myeloma (MM), and discuss the potential use of miRs/nanocarriers association in clinic. Since miRs can act as oncogenes or tumor suppressors, strategies based on their inhibition and/or replacement represent the new opportunities in cancer therapy. The miRs delivery systems include liposomes, polymers, and exosomes that increase their physical stability and prevent nuclease degradation. Phase I/II clinical trials support the importance of miRs as an innovative therapeutic approach in nanomedicine to prevent cancer progression and drug resistance. Results in clinical practice are promising.
Cancer-associated adipocytes have functional roles in tumor development through secreted adipocyte-derived factors and exosomes and also through metabolic symbiosis, where the malignant cells take up ...the lactate, fatty acids and glutamine produced by the neighboring adipocytes. Recent research has demonstrated the value of adipocytes as cell-based delivery platforms for drugs (or prodrugs), nucleic acids or loaded nanoparticles for cancer therapy. This strategy takes advantage of the biocompatibility of the delivery system, its ability to locate the tumor site and also the predisposition of cancer cells to come in functional contact with the adipocytes from the tumor microenvironment for metabolic sustenance. Also, their exosomal content can be used in the context of cancer stem cell reprogramming or as a delivery vehicle for different cargos, like non-coding nucleic acids. Moreover, the process of adipocytes isolation, processing and charging is quite straightforward, with minimal economical expenses. The present review comprehensively presents the role of adipocytes in cancer (in the context of obese and non-obese individuals), the main methods for isolation and characterization and also the current therapeutic applications of these cells as delivery platforms in the oncology sector.
Angiogenesis, which plays an important role in tumor growth and progression of breast cancer, is regulated by a balance between pro- and anti-angiogenic factors. Expression of vascular endothelial ...growth factor (VEGF) is up-regulated during hypoxia by hypoxia-inducible factor-1α (HIF-1α). It is known that there is an interaction between HIF-1α and BRCA1 carrier cancers, but little has been reported about angiogenesis in BRCA1-2 carrier and BRCAX breast cancers. In this study, we investigated the expression of VEGF and HIF-1α and microvessel density (MVD) in 26 BRCA1-2 carriers and 58 BRCAX compared to 77 sporadic breast cancers, by immunohistochemistry. VEGF expression in BRCA1-2 carriers was higher than in BRCAX cancer tissues (p = 0.0001). Furthermore, VEGF expression was higher in both BRCA1-2 carriers and BRCAX than the sporadic group (p<0.0001). VEGF immunoreactivity was correlated with poor tumor grade (p = 0.0074), hormone receptors negativity (p = 0.0206, p = 0.0002 respectively), and MIB-1-labeling index (p = 0.0044) in familial cancers (BRCA1-2 and BRCAX). The percentage of nuclear HIF-1α expression was higher in the BRCA1-2 carriers than in BRCAX cancers (p<0.05), and in all familial than in sporadic tumor tissues (p = 0.0045). A higher MVD was observed in BRCA1-2 carrier than in BRCAX and sporadic cancer tissues (p = 0.002, p = 0.0001 respectively), and in all familial tumors than in sporadic tumors (p = 0.01). MVD was positively related to HIF-1α expression in BRCA1-2 carriers (r = 0.521, p = 0.006), and, in particular, we observed a highly significant correlation in the familial group (r = 0.421, p<0.0001). Our findings suggest that angiogenesis plays a crucial role in BRCA1-2 carrier breast cancers. Prospective studies in larger BRCA1-2 carrier series are needed to improve the best therapeutic strategies for this subgroup of breast cancer patients.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer (BC) is the most common malignancy in women worldwide and leads, in more than 70% of patients with advanced disease, to skeleton colonization and formation of bone metastases (BM). This ...condition implies a severe disability and deterioration of the quality of life, with consequent additional social costs. In recent decades, several studies explored the role of agents acting within the bone microenvironment to counteract BM development, and several bone-targeting agents (BTAs) have been introduced in the clinical practice to manage bone lesions and reduce the risk of skeletal complications. However, long-term exposure to these agents is not free from potential toxicities and needs careful monitoring. In this context, the potential capability to prevent BM onset in selected BC patients, through the early administration of BTAs, has been explored by several researchers, with the belief that "prevention is better than cure" and that, ultimately, metastatic BC is an incurable condition. Here, we revised the mechanisms of BM development in BC as well as the strategies for selecting high-risk patients suitable for early BTA treatment.
We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-βRII. LY2157299 and ...LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Breast cancer is a highly heterogeneous pathology, exhibiting a number of subtypes commonly associated with a poor outcome. Due to their high stability, microRNAs are often regarded as non-invasive ...cancer biomarkers, having an expression pattern specific for their 'cell of origin'.
Triple negative breast cancer (TNBC: ER-, PR-, Her-2-) and double positive breast cancer (DPBC: ER+, PR+, Her-2) miRNA expression patterns were obtained by analysis of the TCGA (The Cancer Genome Atlas) data, followed by PCR-array analysis on plasma samples from 20 TNBC patients, 14 DPBC patients and 11 controls.
Three downregulated and nine upregulated miRNAs were obtained from the TNBC analysis. Five overexpressed miRNAs were identified in the DPBC group. Four of the dysregulated miRNAs (miR-10a, miR-125b, miR-210 and miR-489) were common for both groups. The cluster miR-17-92 (miR-17, miR-20a, miR-20b, and miR-93), along with miR-130, miR-22 and miR-29a/c, were found to differentiate between TNBC and DPBC. A panel of five transcripts (miR-10a, miR-125, miR-193b, miR-200b and miR-489) was validated in a new set of plasma samples. The overlapping of TCGA and plasma profiling data revealed miR-200b, miR-200c, miR-210 and miR-29c as common signature. MiR-200b was validated on additional normal and tumor tissue samples. The expression level of this transcript from the TCGA data was correlated with lung and bone metastatic genes.
The miR-200b presents a great potential for the future advancements in the diagnostic/prognostic and therapeutic approach of TNBC, along with other coding or non-coding transcripts. However, this needs to be further integrated in a regulatory network that acts in conjunction with other markers that affect the patients' prognosis or response to therapy.
In the absence of lymph node abnormalities detectable on clinical examination or imaging, the guidelines provide for the dissection of the first axillary draining lymph nodes during surgery. It is ...not always possible to arrive at surgery without diagnostic doubts, and machine learning algorithms can support clinical decisions. The web calculator CancerMath (CM) allows you to estimate the probability of having positive lymph nodes valued on the basis of tumor size, age, histologic type, grading, expression of estrogen receptor, and progesterone receptor. We collected 993 patients referred to our institute with clinically negative results characterized by sentinel lymph node status, prognostic factors defined by CM, and also human epidermal growth factor receptor 2 (HER2) and Ki-67. Area Under the Curve (AUC) values obtained by the online CM application were comparable with those obtained after training its algorithm on our database. Nevertheless, by training the CM model on our dataset and using the same feature, we reached a sensitivity median value of 72%, whereas the online one was equal to 46%, despite a specificity reduction. We found that the addition of the prognostic factors Her2 and Ki67 could help improve performances on the classification of particular types of patients with the aim of reducing as much as possible the false positives that lead to axillary dissection. As showed by our experimental results, it is not particularly suitable for use as a support instrument for the prediction of metastatic lymph nodes on clinically negative patients.
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