The global burden of cancer attributable to risk factors, 2010-19 : a systematic analysis for the Global Burden of Disease Study 2019

Background Understanding the magnitude of cancer burden attributable to potentially modifiable risk factors is crucial for development of effective prevention and mitigation strategies. We analysed results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2019 to inform cancer control planning efforts globally. Methods The GBD 2019 comparative risk assessment framework was used to estimate cancer burden attributable to behavioural, environmental and occupational, and metabolic risk factors. A total of 82 risk-outcome pairs were included on the basis of the World Cancer Research Fund criteria. Estimated cancer deaths and disability-adjusted life-years (DALYs) in 2019 and change in these measures between 2010 and 2019 are presented. Findings Globally, in 2019, the risk factors included in this analysis accounted for 4.45 million (95% uncertainty interval 4.01-4.94) deaths and 105 million (95.0-116) DALYs for both sexes combined, representing 44.4% (41.3-48.4) of all cancer deaths and 42.0% (39.1-45.6) of all DALYs. There were 2.88 million (2.60-3.18) risk-attributable cancer deaths in males (50.6% [47.8-54.1] of all male cancer deaths) and 1.58 million (1.36-1.84) risk-attributable cancer deaths in females (36.3% [32.5-41.3] of all female cancer deaths). The leading risk factors at the most detailed level globally for risk-attributable cancer deaths and DALYs in 2019 for both sexes combined were smoking, followed by alcohol use and high BMI. Risk-attributable cancer burden varied by world region and Socio-demographic Index (SDI), with smoking, unsafe sex, and alcohol use being the three leading risk factors for risk-attributable cancer DALYs in low SDI locations in 2019, whereas DALYs in high SDI locations mirrored the top three global risk factor rankings. From 2010 to 2019, global risk-attributable cancer deaths increased by 20.4% (12.6-28.4) and DALYs by 16.8% (8.8-25.0), with the greatest percentage increase in metabolic risks (34.7% [27.9-42.8] and 33.3% [25.8-42.0]). Interpretation The leading risk factors contributing to global cancer burden in 2019 were behavioural, whereas metabolic risk factors saw the largest increases between 2010 and 2019. Reducing exposure to these modifiable risk factors would decrease cancer mortality and DALY rates worldwide, and policies should be tailored appropriately to local cancer risk factor burden. Copyright (C) 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.Peer reviewe

Mechanisms of CD8+ T cell exclusion and dysfunction in cancer resistance to anti-PD-(L)1

CD8+ T cells are the front-line defensive cells against cancer. Reduced infiltration and effector function of CD8+ T cells occurs in cancer and is contributed to defective immunity and immunotherapy resistance. Exclusion and exhaustion of CD8+ T cells are the two key factors associated with reduced durability of immune checkpoint inhibitor (ICI) therapy. Initially activated T cells upon exposure to chronic antigen stimulation or immunosuppressive tumor microenvironment (TME) acquire a hyporesponsive state that progressively lose their effector function. Thus, a key strategy in cancer immunotherapy is to look for factors contributed to defective CD8+ T cell infiltration and function. Targeting such factors can define a promising supplementary approach in patients receiving anti-programmed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) therapy. Recently, bispecific antibodies are developed against PD-(L)1 and a dominant factor within TME, representing higher safety profile and exerting more desired outcomes. The focus of this review is to discuss about promoters of deficient infiltration and effector function of CD8+ T cells and their addressing in cancer ICI therapy

Alternative immune checkpoints in immunoregulatory profile of cancer stem cells

Tumor-mediated bypass of immune checkpoint inhibitor (ICI) therapy with anti-programmed death-1 (PD-1), anti-programmed death-ligand 1 (PD-L1, also called B7–H1 or CD274) or anti-cytotoxic T lymphocyte associated antigen-4 (CTLA-4) is a challenge of current years in the area of cancer immunotherapy. Alternative immune checkpoints (AICs) are molecules beyond the common PD-1, PD-L1 or CTLA-4, and are upregulated in patients who show low/no ICI responses. These are members of B7 family including B7–H2 (ICOS-L), B7–H3 (CD276), B7–H4 (B7x), V-domain immunoglobulin suppressor of T cell activation (VISTA), B7–H6, HHLA2 (B7–H5/B7–H7) and catabolic enzymes like indoleamine 2,3-dioxygenase 1 (IDO1), and others that are also contributed to the regulation of tumor immune microenvironment (TIME). There is also strong evidence supporting the implication of AICs in regulation of cancer stemness and expanding the population of cancer stem cells (CSCs). CSCs display immunoregulatory capacity and represent multiple immune checkpoints either on their surface or inside. Besides, they are active promoters of resistance to the common ICIs. The aim of this review is to investigate interrelations between AICs with stemness and differentiation profile of cancer. The key message of this paper is that targeted checkpoints can be selected based on their impact on CSCs along with their effect on immune cells. Studies published so far mainly focused on immune cells as a target for anti-checkpoints. Ex vivo engineering of extracellular vesicles (EVs) equipped with CSC-targeted anti-checkpoint antibodies is without a doubt a key therapeutic target that can be under consideration in future research

The impact of oncolytic adenoviral therapy on the therapeutic efficacy of PD-1/PD-L1 blockade

Immunotherapy has revolutionized treatment of cancer during the last decades. Oncolytic virotherapy has also emerged as a strategy to fight against cancer cells both via lysis of malignant cells and activating immune responses. Accepted as a logical strategy, combination of monoclonal antibodies particularly against the programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) is introduced to improve clinical responses to immune checkpoint inhibitors (ICIs). Accordingly, Talimogene laherparepvec (T-VEC) has received approval for clinical use, while a number of oncolytic Adenoviruses (Ads) are being investigated in clinical trials of malignancies. Combination of oncolytic Ads with PD-1/PD-L1 inhibitors have shown potentials in promoting responses to ICIs, changing the tumor microenvironment, inducing long-term protection against tumor, and promoting survival among mice models of malignancies. Regarding the increasing importance of oncolytic Ads in combination therapy of cancers, in this review we decide to outline recent studies in this field

Strategies for Application of Extracellular Vesicles in Solid Cancer Therapy

Background and Aim: Extracellular vesicles (EVs) are key players in cellular communication and signaling in the health status and diseases. EVs have rather small size and long half-life upon secretion into circulation. This long half-life along with their immune privileged profile and the ability to carry biotherapeutics to the target cells have made EVs an issue of prominent current interest among scientists as an alternative schedule in cancer therapy. Materials and Methods: PubMed and Google scholar were searched for relevant articles from journals with high impact factor. Among 400 articles found, 40 articles met the criteria for interpretation and were selected for descriptive review. Original and review articles published in the last ten years were used in this study. Results: Tumor-derived EVs can be targeted for reducing cancer cell survival and increasing their apoptosis. They are also applicable for drug delivery to primary or metastatic tumors. An effective approach is to load nanoparticles into EVs for targeting a specific cell type in tumor ecosystem. Their application in nano delivery systems for cancer therapy has been the focus of attention. Conclusion: The current studies have focused on the possibility of using EVs as biomarkers in several diseases, as targets to be removed for recovery of the patient health, and as vehicles for immunotherapy. In this review article, we discussed the importance of EV suppression or EV-based strategy for targeting solid cancer

Bypassing anti-PD-(L)1 therapy: Mechanisms and management strategies

Resistance to immune checkpoint inhibitors (ICIs) is a major issue of the current era in cancer immunotherapy. Immune evasion is a multi-factorial event, which occurs generally at a base of cold immunity. Despite advances in the field, there are still unsolved challenges about how to combat checkpoint hijacked by tumor cells and what are complementary treatment strategies to render durable anti-tumor outcomes. A point is that anti-programed death-1 receptor (PD-1)/anti-programmed death-ligand 1 (PD-L1) is not the solo path of immune escape, and responses in many types of solid tumors to the PD-1/PD-L1 inhibitors are not satisfactory. Thus, seeking mechanisms inter-connecting tumor with its immune ecosystem nearby unravel more about resistance mechanisms so as to develop methods for sustained reinvigoration of immune activity against cancer. In this review, we aimed to discuss about common and specific paths taken by tumor cells to evade immune surveillance, describing novel detection strategies, as well as suggesting some approaches to recover tumor sensitivity to the anti-PD-(L)1 therapy based on the current knowledge

The emerging role of non-coding RNAs in the regulation of PI3K/AKT pathway in the carcinogenesis process

The PI3K/AKT pathway is an intracellular signaling pathway with an indispensable impact on cell cycle control. This pathway is functionally related with cell proliferation, cell survival, metabolism, and quiescence. The crucial role of this pathway in the development of cancer has offered this pathway as a target of novel anti-cancer treatments. Recent researches have demonstrated the role of microRNAs (miRNAs) and long noncoding RNAs (lncRNAs) in controlling the PI3K/AKT pathway. Some miRNAs such as miR-155-5p, miR-328-3p, miR-125b-5p, miR-126, miR-331-3p and miR-16 inactivate this pathway, while miR-182, miR-106a, miR-193, miR-214, miR-106b, miR-93, miR-21 and miR-103/107 enhance activity of this pathway. Expression levels of PI3K/AKT-associated miRNAs could be used to envisage the survival of cancer patients. Numerous lncRNAs such as GAS5, FER1L4, LINC00628, PICART1, LOC101928316, ADAMTS9-AS2, SLC25A5-AS1, MEG3, AB073614 and SNHG6 interplay with this pathway. Identification of the impact of miRNAs and lncRNAs in the control of the activity of PI3K/AKT pathway would enhance the efficacy of targeted therapies against this pathway. Moreover, each of the mentioned miRNAs and lncRNAs could be used as a putative therapeutic candidate for the interfering with the carcinogenesis. In the current study, we review the role of miRNAs and lncRNAs in controlling the PI3K/AKT pathway and their contribution to carcinogenesis

Different types of bisphenols alter ovarian steroidogenesis: Special attention to BPA

Endocrine disruptors such as bisphenol A (BPA) and some of its analogues, including BPS, BPAF, and BPE, are used extensively in the manufacture of plastics. These synthetic chemicals could seriously alter the functionality of the female reproductive system. Although the number of studies conducted on other types of bisphenols is smaller than the number of studies on BPA, the purpose of this review study was to evaluate the effects of bisphenol compounds, particularly BPA, on hormone production and on genes involved in ovarian steroidogenesis in both in vitro (human and animal cell lines) and in vivo (animal models) studies.The current data show that exposure to bisphenol compounds has adverse effects on ovarian steroidogenesis. For example, BPA, BPS, and BPAF can alter the normal function of the hypothalamic-pituitary-gonadal (HPG) axis by targeting kisspeptin neurons involved in steroid feedback signals to gonadotropin-releasing hormone (GnRH) cells, resulting in abnormal production of LH and FSH. Exposure to BPA, BPS, BPF, and BPB had adverse effects on the release of some hormones, namely 17-β-estradiol (E2), progesterone (P4), and testosterone (T). BPA, BPE, BPS, BPF, and BPAF are also capable of negatively altering the transcription of a number of genes involved in ovarian steroidogenesis, such as the steroidogenic acute regulatory protein (StAR, involved in the transfer of cholesterol from the outer to the inner mitochondrial membrane, where the steroidogenesis process begins), cytochrome P450 family 17 subfamily A member 1 (Cyp17a1, which is involved in the biosynthesis of androgens such as testosterone), 3 beta-hydroxysteroid dehydrogenase enzyme (3β-HSD, involved in the biosynthesis of P4), and cytochrome P450 family 19 subfamily A member 1 (Cyp19a1, involved in the biosynthesis of E2). Exposure to BPA, BPB, BPF, and BPS at prenatal or prepubertal stages could decrease the number of antral follicles by activating apoptosis and autophagy pathways, resulting in decreased production of E2 and P4 by granulosa cells (GCs) and theca cells (TCs), respectively. BPA and BPS impair ovarian steroidogenesis by reducing the function of some important cell receptors such as estrogens (ERs, including ERα and ERβ), progesterone (PgR), the orphan estrogen receptor gamma (ERRγ), the androgen receptor (AR), the G protein-coupled estrogen receptor (GPER), the FSHR (follicle-stimulating hormone receptor), and the LHCGR (luteinizing hormone/choriogonadotropin receptor). In animal models, the effects of bisphenol compounds depend on the type of animals, their age, and the duration and dose of bisphenols, while in cell line studies the duration and doses of bisphenols are the matter