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Simple Summary: The most common adverse events (AEs) that occurred in response to targeted therapy for hepatocellular carcinoma were appetite loss (adverse event grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). Among these, appetite loss and general fatigue negatively affect overall survival (OS) and progression-free survival (PFS). Increasing AE grades of hypertension, proteinuria, and hypothyroidism were associated with better OS, whereas hypertension, HFS, and hypothyroidism were associated with better PFS. To assess the impact of adverse event (AE) severity, caused by targeted therapy, on overall survival (OS) and progression-free survival (PFS) in patients with unresectable hepatocellular carcinoma (HCC), a total of 183 patients with HCC treated with atezolizumab plus bevacizumab (40), lenvatinib (57), sorafenib (79), cabozantinib (3), ramucirumab (3), and regorafenib (1) were included in this study. Age-, AFP-, and ALBI score-adjusted hazard ratios (HRs) of AE grades 1 to 3 versus grade 0 for OS and PFS were calculated using Cox proportional hazards models. The linear trend of the HRs was assessed by calculating the p values for this trend. The most common AEs were appetite loss (AE grade 0/1/2/3 = 97/23/55/12), general fatigue (102/31/44/6), hypertension (120/6/40/17), hand-foot syndrome (HFS) (135/21/24/3), proteinuria (140/13/16/14), and hypothyroidism (148/12/23/0). The adjusted HRs for OS of these AEs were 0.532–1.450–2.361 (p for trend 0.037), 1.057–1.691–3.364 (p for trend 0.004), 1.176–0.686–0.281 (p for trend 0.002), 0.639–0.759–1.820 (p for trend 0.462), 1.030–0.959–0.147 (p for trend 0.011), and 0.697–0.609 (p for trend 0.119), respectively. Those for PFS of the corresponding AEs were 0.592–1.073–2.811 (p for trend 0.255), 1.161–1.282–4.324 (p for trend 0.03), 0.965–0.781–0.655 (p for trend 0.095), 0.737–0.623–2.147 (p for trend 0.153), 1.061–0.832–0.800 (p for trend 0.391), and 1.412–0.560 (p for trend 0.081), respectively. Appetite loss and general fatigue negatively affected clinical outcomes, whereas hypertension, HFS, proteinuria, and hypothyroidism had positive effects. [ABSTRACT FROM AUTHOR]

Simple Summary: This review is centered on the potential therapeutic utility of vitamin C (VC) in the context of dynamic cancer evolution. Physiologically, VC has dose-dependent roles as both an antioxidant and a pro-oxidant and has been associated with various health benefits, including potential applications in cancer management. Its intriguing ability to selectively target cancer cells has sparked recent research exploring its potential use against cancer stem cells (CSCs), a crucial player in both tumorigenesis and metastasis. CSCs play a pivotal role in tumor progression, metastasis, and resistance to conventional drug treatments. This review seeks to elucidate the underlying mechanisms by which VC effectively targets and reduces the activity of CSCs, thereby providing important insights and rationale for the improvement of anti-cancer therapeutic strategies. Vitamin C (VC) is an essential nutrient that is vital for maintaining cellular physiology. Interestingly, it functions as either an antioxidant or a pro-oxidant, depending on the concentration used. At high-doses, VC selectively targets various cancer cell types through its pro-oxidant action, while at low-doses, VC enhances anti-tumor immunity by acting as an antioxidant. This versatility makes VC a promising anti-tumor agent for both standalone and combination therapies. Tumors consist of diverse cancer cell subtypes with distinct phenotypic and functional characteristics. In particular, cancer stem cells (CSCs), which are self-renewing multi-potent cells, are responsible for tumor recurrence, metastasis, chemoresistance, and heightened mortality. CSCs are often associated with the epithelial–mesenchymal transition (EMT), which confers increased motility and invasive capabilities that are characteristic of malignant and drug-resistant cells. Thus, eradicating CSC populations is crucial and has led to extensive efforts aimed at identifying medicines that can target them. Recent studies suggest that VC can selectively target CSCs via epigenetic and metabolic pathways in various cancers. Here, we highlight recent progress that has been made in understanding how VC effectively targets CSC evolution, providing a rationale for the use of VC either alone or in combination with other treatments to improve outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: Although sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reported to affect therapeutic efficacy and the occurrence of adverse events in sorafenib or lenvatinib treatment for hepatocellular carcinoma (HCC), there is considerably less evidence regarding the relationship between SMI and prognosis in the HCC patients treated with atezolizumab plus bevacizumab (atezo/bev) therapy. Furthermore, there are no reports of muscle strength, including grip strength (GS), which is essential for an accurate diagnosis of sarcopenia. This is the first study to show the relationship between sarcopenia, diagnosed by decreased GS and SMI, and clinical outcomes in atezo/bev therapy, with novel evidence having a strong impact. The presence of sarcopenia is significantly associated with shorter overall survival with the occurrence of adverse events and decreased liver function. Monitoring of both GS and SMI is useful for assessing the general condition and predicting prognosis in HCC patients treated with atezo/bev therapy. Although there have been advances in the prevention and diagnosis of hepatocellular carcinoma (HCC) in recent years, many HCC patients are still diagnosed with advanced stage. Systemic therapy is indicated for unresectable HCC (uHCC) with major vascular invasion and/or extrahepatic metastases, and the atezolizumab plus bevacizumab (atezo/bev) combination is currently recommended as first-line treatment for uHCC. Recently, sarcopenia-related factors, including decreased skeletal muscle index (SMI), have been reportedly associated with prognosis in uHCC patients treated with sorafenib or lenvatinib. There are few reports on muscle strength assessments, including grip strength (GS), despite their importance in accurate sarcopenia diagnosis, and furthermore, there is no evidence regarding atezo/bev therapy. In this study, we investigated whether sarcopenia affects the clinical outcome of atezo/bev therapy. This study included 64 uHCC patients on atezo/bev therapy and assessed their GS and SMI, and SMI was measured using bioelectrical impedance analysis (BIA). We diagnosed sarcopenia based on GS and BIA-SMI and compared the clinical outcomes in the sarcopenia and non-sarcopenia groups. Of these patients, 28 had sarcopenia, and 36 had non-sarcopenia. Adverse events (AEs) frequently occurred, and the albumin-bilirubin score significantly decreased after atezo/bev therapy in the sarcopenia group than in the non-sarcopenia group. The median progression-free survival was 4.7 (0.4–26.4) and 10.6 (1.1–24.5) months in the sarcopenia and non-sarcopenia groups, respectively. The median overall survival (OS) was 12.6 (1.4–27.7) months in the sarcopenia group and was not reached in the non-sarcopenia group, indicating a significant difference in the Kaplan-Meier survival curves for both groups (p < 0.01). In multivariate analysis, sarcopenia was significantly associated with OS. In conclusion, sarcopenia was significantly associated with poor clinical outcomes based on the occurrence of AEs and decreased liver function in uHCC patients on atezo/bev therapy. GS and SMI are important parameters for accurately diagnosing sarcopenia. [ABSTRACT FROM AUTHOR]

Simple Summary: Although immunotherapy has improved the treatment and outcome of cancer patients, there are still limitations to face because most patients cannot receive lasting benefits. We believe it is urgent to discover new potential biomarkers and therapeutic targets for investigating personalized and less invasive anticancer treatments. In the present paper, we highlight: (i) the impact of ubiquitination and its reverse, de-ubiquitination, in orchestrating the immune response of the tumor microenvironment; (ii) selected clinical trials, which provide information on combination cancer immunotherapy and new immunomodulatory targets; (iii) current challenges in immunotherapy, including imaging technologies and ROS-based immunotherapies, as well as immunotherapy side effects. Finally, the major outstanding questions in cancer immunotherapy are also presented, and directions for future research are described. Immunotherapy is a cancer treatment that exploits the capacity of the body's immune system to prevent, control, and remove cancer. Immunotherapy has revolutionized cancer treatment and significantly improved patient outcomes for several tumor types. However, most patients have not benefited from such therapies yet. Within the field of cancer immunotherapy, an expansion of the combination strategy that targets independent cellular pathways that can work synergistically is predicted. Here, we review some consequences of tumor cell death and increased immune system engagement in the modulation of oxidative stress and ubiquitin ligase pathways. We also indicate combinations of cancer immunotherapies and immunomodulatory targets. Additionally, we discuss imaging techniques, which are crucial for monitoring tumor responses during treatment and the immunotherapy side effects. Finally, the major outstanding questions are also presented, and directions for future research are described. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last decade, proteasome inhibitors have become a standard treatment for multiple myeloma. However, resistance to combined therapies remains a challenge due to the disease's complex biology, crosstalk with the bone marrow microenvironment, and toxicities. To address this issue, high-throughput functional approaches are identifying new synthetic lethal interactions. In this study, a library of small-molecule inhibitors was used to identify compounds that could enhance the efficacy of proteasome inhibitors in multiple myeloma. The results suggest that EHMT2 inhibition could be a feasible strategy to increase proteasome inhibitor sensitivity and overcome drug resistance in multiple myeloma patients. Proteasome inhibitors (PIs) are extensively used for the therapy of multiple myeloma. However, patients continuously relapse or are intrinsically resistant to this class of drugs. In addition, adverse toxic effects such as peripheral neuropathy and cardiotoxicity could arise. Here, to identify compounds that can increase the efficacy of PIs, we performed a functional screening using a library of small-molecule inhibitors covering key signaling pathways. Among the best synthetic lethal interactions, the euchromatic histone-lysine N-methyltransferase 2 (EHMT2) inhibitor UNC0642 displayed a cooperative effect with carfilzomib (CFZ) in numerous multiple myeloma (MM) cell lines, including drug-resistant models. In MM patients, EHMT2 expression correlated to worse overall and progression-free survival. Moreover, EHMT2 levels were significantly increased in bortezomib-resistant patients. We demonstrated that CFZ/UNC0642 combination exhibited a favorable cytotoxicity profile toward peripheral blood mononuclear cells and bone-marrow-derived stromal cells. To exclude off-target effects, we proved that UNC0642 treatment reduces EHMT2-related molecular markers and that an alternative EHMT2 inhibitor recapitulated the synergistic activity with CFZ. Finally, we showed that the combinatorial treatment significantly perturbs autophagy and the DNA damage repair pathways, suggesting a multi-layered mechanism of action. Overall, the present study demonstrates that EHMT2 inhibition could provide a valuable strategy to enhance PI sensitivity and overcome drug resistance in MM patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite clinical success, only a limited percentage of cancer patients are responsive to immunotherapy. Recently, gut microbiota modulation has been suggested as a tool to enhance immunotherapy efficacy, and mechanisms for these effects may be linked to microbial contributions—such as microbial-derived vitamins—to immune responses. While humans can acquire their vitamins from dietary sources, gut microbial-derived vitamins are crucial to the immune system's function. The production of these vitamins can be altered by the bidirectional crosstalk between the immune system and the gut microbiome; however, their exact mechanism of action in bacterial communities and immune responses remains elusive. Further studies and clinical trials are needed to understand the role of microbial-derived vitamins in anti-tumor immune responses and their role in the efficacy of immunotherapies. This review will discuss the in-depth mechanisms of selective vitamins and their role in modulating immune responses, as well as their potential as immunotherapy enhancers. Not all cancer patients who receive immunotherapy respond positively and emerging evidence suggests that the gut microbiota may be linked to treatment efficacy. Though mechanisms of microbial contributions to the immune response have been postulated, one likely function is the supply of basic co-factors to the host including selected vitamins. Bacteria, fungi, and plants can produce their own vitamins, whereas humans primarily obtain vitamins from exogenous sources, yet despite the significance of microbial-derived vitamins as crucial immune system modulators, the microbiota is an overlooked source of these nutrients in humans. Microbial-derived vitamins are often shared by gut bacteria, stabilizing bioenergetic pathways amongst microbial communities. Compositional changes in gut microbiota can affect metabolic pathways that alter immune function. Similarly, the immune system plays a pivotal role in maintaining the gut microbiota, which parenthetically affects vitamin biosynthesis. Here we elucidate the immune-interactive mechanisms underlying the effects of these microbially derived vitamins and how they can potentially enhance the activity of immunotherapies in cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic carcinoma is one of the malignancies with the highest cancer-specific mortality. While invading the microenvironment and the dense stroma, the immune system plays a key role in the pathological development, as well as in the treatment of pancreatic tumors. In this review, evidence-based treatment options, including standard oncological treatment and integrative therapies, such as hyperthermia, electroporation, intra-tumoral injections, phytochemical preparations or vitamins to improve the prognosis of patients with pancreatic cancer, are presented and discussed. Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here. [ABSTRACT FROM AUTHOR]

Simple Summary: Pain associated with cancer diagnoses is a serious concern and one of the most common symptoms reported by cancer patients. The insufficient relief of cancer pain can have a major impact on patients' quality of life. Recent developments in oncology such as new pain management guidelines, drugs and treatment strategies may have had a positive effect on the prevalence and severity of pain. Therefore, the aim of this systematic literature review was to assess the prevalence of pain and pain severity in cancer patients throughout all phases of treatment in the 2014–2021 literature period. Our results show a decline in both the prevalence and severity of cancer pain, compared to previous research. Nevertheless, with 44.5% of cancer patients still experiencing pain, the prevalence remains high, emphasizing the need for ongoing attention regarding the management of cancer pain. Experiencing pain and insufficient relief can be devastating and negatively affect a patient's quality of life. Developments in oncology such as new treatments and adjusted pain management guidelines may have influenced the prevalence of cancer pain and severity in patients. This review aims to provide an overview of the prevalence and severity of pain in cancer patients in the 2014–2021 literature period. A systematic literature search was performed using the databases PubMed, Embase, CINAHL, and Cochrane. Titles and abstracts were screened, and full texts were evaluated and assessed on methodological quality. A meta-analysis was performed on the pooled prevalence and severity rates. A meta-regression analysis was used to explore differences between treatment groups. We identified 10,637 studies, of which 444 studies were included. The overall prevalence of pain was 44.5%. Moderate to severe pain was experienced by 30.6% of the patients, a lower proportion compared to previous research. Pain experienced by cancer survivors was significantly lower compared to most treatment groups. Our results imply that both the prevalence of pain and pain severity declined in the past decade. Increased attention to the assessment and management of pain might have fostered the decline in the prevalence and severity of pain. [ABSTRACT FROM AUTHOR]

Simple Summary: Microtubule-targeting agents are a class of chemotherapeutics used to treat triple-negative breast cancer (TNBC). These include drugs such as eribulin that depolymerize microtubules, as well as microtubule stabilizing taxanes such as paclitaxel. TNBC is a relatively immunogenic form of breast cancer and one strategy to further increase immunogenicity is through activation of the cGAS-STING innate immune sensing pathway. We demonstrate that eribulin enhances interferon production in combination with STING agonists undergoing clinical development in immune and TNBC cells. This phenotype is shared with other microtubule destabilizers, but not with stabilizers, suggesting a mechanism downstream of microtubule depolymerization. We determined that eribulin also enhanced immunogenic responses in vivo and improved antitumor efficacy in a spontaneous murine mammary tumor model when combined with a STING agonist. These findings highlight important mechanistic distinctions between microtubule targeted chemotherapeutic drugs and provide an opportunity to improve the efficacy of immunotherapies using a compound currently used in TNBC. Eribulin is a microtubule destabilizer used in the treatment of triple-negative breast cancer (TNBC). Eribulin and other microtubule targeted drugs, such as the taxanes, have shared antimitotic effects, but differ in their mechanism of microtubule disruption, leading to diverse effects on cellular signaling and trafficking. Herein, we demonstrate that eribulin is unique from paclitaxel in its ability to enhance expression of the immunogenic cytokine interferon beta (IFNβ) in combination with STING agonists in both immune cells and TNBC models, including profound synergism with ADU-S100 and E7766, which are currently undergoing clinical trials. The mechanism by which eribulin enhances STING signaling is downstream of microtubule disruption and independent of the eribulin-dependent release of mitochondrial DNA. Eribulin did not override the requirement of ER exit for STING activation and did not inhibit subsequent STING degradation; however, eribulin significantly enhanced IRF3 phosphorylation and IFNβ production downstream of the RNA sensing pathway that converges on this transcription factor. Additionally, we found that eribulin enhanced the population of activated CD4+ T-cells in vivo when combined with either a STING agonist or tumor, demonstrating the ability to function as an immune adjuvant. We further interrogated the combination of eribulin with ADU-S100 in the MMTV-PyVT spontaneous murine mammary tumor model where we observed significant antitumor efficacy with combination treatment. Together, our findings demonstrate that microtubule targeted chemotherapeutics have distinct immunological effects and that eribulin's ability to enhance innate immune sensing pathways supports its use in combination with immunotherapies, such as STING agonists, for the more effective treatment of TNBC and other malignancies. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastasis refers to the progressive dissemination of primary tumor cells and their colonization of other tissues, and is a major cause of treatment failure in cancer patients. Most cancers metastasize to specific organs with a non-random distribution pattern through a process known as "organ-specific metastasis". Extracellular vesicles (EVs), mediating intercellular communication, can deliver ncRNAs to regulate cancer phenotypes at distant organs or sites in multiple cancers, thereby contributing to organ-specific metastasis. This review summarizes the underlying mechanisms and functions of EV-ncRNA-mediated metastatic organotropism in bone, liver, lung, brain, and lymphatic metastasis, and highlights the clinical applications of EV-ncRNAs serving as potential biomarkers and therapeutic targets. The aim of this review is to provide a perspective on the novel therapeutic strategies of organ-specific metastasis and hope for improving the survival outcome of cancer patients. Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as "organ-specific metastasis". Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer metabolism is an emerging field of investigation aimed at identifying cancer cell vulnerabilities in order to define novel anti-cancer therapeutic approaches based on interventions that modulate the availability of specific nutrients. Amino acids (AAs) are used by cancer cells as both building blocks for protein synthesis required for rapid tumor growth and as sources of energy. The current review aims to describe the most relevant alterations of AA metabolism that could be targeted by either AA deprivation or AA supplementation to limit tumor growth. In parallel, the reader will understand how AA availability mainly relies on and impacts cancer-host metabolism, eventually leading to a wasting paraneoplastic syndrome called cachexia. The above-mentioned AA-based interventions are here discussed also in view of their impact on the tumor host, in an attempt to provide a broader view that can improve our understanding of the patient outcome. Rapid tumor growth requires elevated biosynthetic activity, supported by metabolic rewiring occurring both intrinsically in cancer cells and extrinsically in the cancer host. The Warburg effect is one such example, burning glucose to produce a continuous flux of biomass substrates in cancer cells at the cost of energy wasting metabolic cycles in the host to maintain stable glycemia. Amino acid (AA) metabolism is profoundly altered in cancer cells, which use AAs for energy production and for supporting cell proliferation. The peculiarities in cancer AA metabolism allow the identification of specific vulnerabilities as targets of anti-cancer treatments. In the current review, specific approaches targeting AAs in terms of either deprivation or supplementation are discussed. Although based on opposed strategies, both show, in vitro and in vivo, positive effects. Any AA-targeted intervention will inevitably impact the cancer host, who frequently already has cachexia. Cancer cachexia is a wasting syndrome, also due to malnutrition, that compromises the effectiveness of anti-cancer drugs and eventually causes the patient's death. AA deprivation may exacerbate malnutrition and cachexia, while AA supplementation may improve the nutritional status, counteract cachexia, and predispose the patient to a more effective anti-cancer treatment. Here is provided an attempt to describe the AA-based therapeutic approaches that integrate currently distant points of view on cancer-centered and host-centered research, providing a glimpse of several potential investigations that approach cachexia as a unique cancer disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is a systemic therapy significant for numerous types of cancer. The search for factors which may improve the effectiveness of the therapy is still ongoing. The correlation between host microbiome and the efficacy of immunotherapy has been confirmed. Nutrients modulate the composition of the microbiome, which can be used to improve treatment. The paper presents the impact of probiotics, prebiotics and micronutrients on particular species of bacteria associated with a significant increase in response to anti-PD1, anti-PD-L1 and anti-CTLA4 immunotherapy. We also present our own investigation on the relationship between the gut microbiome and the effectiveness of immunotherapy in non-small-cell lung cancer patients. The effectiveness of immunotherapy in cancer patients depends on the activity of the host's immune system. The intestinal microbiome is a proven immune system modulator, which plays an important role in the development of many cancers and may affect the effectiveness of anti-cancer therapy. The richness of certain bacteria in the gut microbiome (e.g., Bifidobacterium spp., Akkermanisa muciniphila and Enterococcus hire) improves anti-tumor specific immunity and the response to anti-PD-1 or anti-PD-L1 immunotherapy by activating antigen-presenting cells and cytotoxic T cells within the tumor. Moreover, micronutrients affect directly the activities of the immune system or regulate their function by influencing the composition of the microbiome. Therefore, micronutrients can significantly influence the effectiveness of immunotherapy and the development of immunorelated adverse events. In this review, we describe the relationship between the supply of microelements and the abundance of various bacteria in the intestinal microbiome and the effectiveness of immunotherapy in cancer patients. We also point to the function of the immune system in the case of shifts in the composition of the microbiome and disturbances in the supply of microelements. This may in the future become a therapeutic target supporting the effects of immunotherapy in cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is a malignant hematological disease whose pathomechanism is not yet fully understood on the molecular level. Extracellular vesicles might be of significance in the evolution of this disease. Our aim is to present and systematize the latest findings concerning the role of extracellular vesicles in multiple myeloma, in order to enable an easier establishment of new research aims in this area. The results of such research could contribute to a better understanding of the disease and in consequence, result in the improvement of the diagnostic process of multiple myeloma and the invention of new therapies. Multiple myeloma (MM) is a plasma cell-derived malignancy that stands for around 1.5% of newly discovered cancer cases. Despite constantly improving treatment methods, the disease is incurable with over 13,000 deaths in the US and over 30,000 in Europe. Recent studies suggest that extracellular vesicles (EVs) might play a significant role in the pathogenesis and evolution of MM. Further investigation of their role could prove to be beneficial in establishing new therapies and hence, improve the prognosis of MM patients. What is more, EVs might serve as novel markers in diagnosing and monitoring the disease. Great advancements concerning the position of EVs in the pathophysiology of MM have recently been shown in research and in this review, we would like to delve into the still expanding state of knowledge. [ABSTRACT FROM AUTHOR]

Simple Summary: The tumor microenvironment (TME) is a complicated network, and several promising TME-targeted therapies, such as immunotherapy and targeted therapies, are now facing problems over low response rates and drug resistance. Vitamin C (VitC) has been extensively studied as a dietary nutrient and multi-targeted natural drug for fighting against tumor cells. The focus has been recently on its crucial functions in the TME. Here, we discuss the potential mechanisms of VitC in several specialized microenvironments, characterize the current status of its preclinical and clinical applications, and offer suggestions for future studies. This article is intended to provide basic researchers and clinicians with a detailed picture of VitC targeting the tumor microenvironment. Based on the enhanced knowledge on the tumor microenvironment (TME), a more comprehensive treatment landscape for targeting the TME has emerged. This microenvironment provides multiple therapeutic targets due to its diverse characteristics, leading to numerous TME-targeted strategies. With multifaced activities targeting tumors and the TME, vitamin C is renown as a promising candidate for combination therapy. In this review, we present new advances in how vitamin C reshapes the TME in the immune, hypoxic, metabolic, acidic, neurological, mechanical, and microbial dimensions. These findings will open new possibilities for multiple therapeutic avenues in the fight against cancer. We also review the available preclinical and clinical evidence of vitamin C combined with established therapies, highlighting vitamin C as an adjuvant that can be exploited for novel therapeutics. Finally, we discuss unresolved questions and directions that merit further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Dendritic cells (DCs) are an important type of immune cell present in the blood and tissues, capable of detecting potential threats and displaying them to lymphocytes in the lymph nodes, therefore initiating lymphocyte-mediated responses. DCs not only recognize pathogens but also damaged or altered cells from our own bodies, such as cancer cells, and contribute to the immune response to cancer. However, the tumor microenvironment, the environment that surrounds cancer cells, produces a number of factors that can modulate the function of DCs, which can acquire an immunosuppressive phenotype that allows tumor growth. This acquisition is also tightly regulated by epigenetics, the set of mechanisms that impact gene function without altering the DNA sequence. In this review, we discuss epigenetic mechanisms that influence the development of functional DCs and their altered function in the tumor microenvironment. We propose how this knowledge can be used both to epigenetically modulate these cells, and for the development of DC-based vaccine therapies. Dendritic cells (DCs) are professional antigen-presenting cells with the distinctive property of inducing the priming and differentiation of naïve CD4+ and CD8+ T cells into helper and cytotoxic effector T cells to develop efficient tumor-immune responses. DCs display pathogenic and tumorigenic antigens on their surface through major histocompatibility complexes to directly influence the differentiation of T cells. Cells in the tumor microenvironment (TME), including cancer cells and other immune-infiltrated cells, can lead DCs to acquire an immune-tolerogenic phenotype that facilitates tumor progression. Epigenetic alterations contribute to cancer development, not only by directly affecting cancer cells, but also by their fundamental role in the differentiation of DCs that acquire a tolerogenic phenotype that, in turn, suppresses T cell-mediated responses. In this review, we focus on the epigenetic regulation of DCs that have infiltrated the TME and discuss how knowledge of the epigenetic control of DCs can be used to improve DC-based vaccines for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy is a rapidly advancing field in breast cancer treatment, however, it encounters many obstacles that leave open gateways for breast cancer cells to resist novel immunotherapies. It is believed that the tumor microenvironment consisting of cancer, stromal, and immune cells as well as a plethora of tumor-promoting soluble factors, is responsible for the failure of therapeutic strategies in cancer, including breast tumors. Therefore, an in-depth understanding of key barriers to effective immunotherapy, focusing the research efforts on harnessing the power of the immune system, and thus, developing new strategies to overcome the resistance may contribute significantly to increase breast cancer patient survival. In this review, we discuss the latest reports regarding the strategies rendering the immunosuppressive tumor microenvironment more sensitive to immunotherapy in breast cancers, HER2-positive and triple-negative types of breast cancer, which are attractive from an immunotherapeutic point of view. Breast cancer (BC) has traditionally been considered to be not inherently immunogenic and insufficiently represented by immune cell infiltrates. Therefore, for a long time, it was thought that the immunotherapies targeting this type of cancer and its microenvironment were not justified and would not bring benefits for breast cancer patients. Nevertheless, to date, a considerable number of reports have indicated tumor-infiltrating lymphocytes (TILs) as a prognostic and clinically relevant biomarker in breast cancer. A high TILs expression has been demonstrated in primary tumors, of both, HER2-positive BC and triple-negative (TNBC), of patients before treatment, as well as after treatment with adjuvant and neoadjuvant chemotherapy. Another milestone was reached in advanced TNBC immunotherapy with the help of the immune checkpoint inhibitors directed against the PD-L1 molecule. Although those findings, together with the recent developments in chimeric antigen receptor T cell therapies, show immense promise for significant advancements in breast cancer treatments, there are still various obstacles to the optimal activity of immunotherapeutics in BC treatment. Of these, the immunosuppressive tumor microenvironment constitutes a key barrier that greatly hinders the success of immunotherapies in the most aggressive types of breast cancer, HER2-positive and TNBC. Therefore, the improvement of the current and the demand for the development of new immunotherapeutic strategies is strongly warranted. [ABSTRACT FROM AUTHOR]

Simple Summary: The interest in the biological role and clinical impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is continuously expanding. Many studies, mainly involving solid tumors, have strongly suggested the MIAT oncogenic role; more recently, it has been suggested that MIAT may have a role in inducing Bortezomib resistance in MM. However, data concerning MIAT deregulation in MM are virtually absent. In this context, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. Our findings prompt further studies to elucidate better the significance of MIAT in MM. The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an essential aspect of the investigation, which may contribute to understanding the disease's complex pathobiology, providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the clinical relevance of the lncRNA MIAT in MM, taking advantage of the publicly available CoMMpass database. MIAT expression in MM is highly heterogeneous and significantly associated with specific molecular lesions frequently occurring in MM. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of MIAT in different signaling pathways and ribosome biogenesis and assembly. These findings suggest that MIAT deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and, indirectly, the translational process. Although MIAT expression levels seem not to be significantly associated with clinical outcome in multivariate analyses, high MIAT expression levels are associated with bortezomib resistance, this suggesting that MIAT targeting could overcome drug resistance in MM. These findings strongly prompt for further studies investigating the significance of MIAT in MM. [ABSTRACT FROM AUTHOR]

Simple Summary: The growing interest in BCL2 inhibitors for the treatment of multiple myeloma (MM) has led to the need for biomarkers that are able to predict patient's sensitivity to the drug. The presence of the chromosomal translocation t(11;14) in MM is mainly associated with sensitivity to venetoclax and good prognosis. The incidence of t(11;14) largely increases in primary Plasma Cell Leukemia (pPCL) in association with an unfavorable outcome. Currently, data concerning pPCL sensitivity to venetoclax are virtually absent. In this context, we investigated the transcriptome of MM and pPCL with t(11;14), evidencing that the two clinical entities are likely responsive to venetoclax based on different molecular programs, thus prompting further studies to elucidate better novel potential predictive biomarkers. Mechanisms underlying the pathophysiology of primary Plasma Cell Leukemia (pPCL) and intramedullary multiple myeloma (MM) need to be further elucidated, being potentially relevant for improving therapeutic approaches. In such a context, the MM and pPCL subgroups characterized by t(11;14) deserve a focused investigation, as the presence of the translocation is mainly associated with sensitivity to venetoclax. Herein, we investigated a proprietary cohort of MM and pPCL patients, focusing on the transcriptional signature of samples carrying t(11;14), whose incidence increases in pPCL in association with an unfavorable outcome. In addition, we evaluated the expression levels of the BCL2-gene family members and of a panel of B-cell genes recently reported to be associated with sensitivity to venetoclax in MM. Moreover, transcriptional analysis of lncRNAs in the two clinical settings led to the identification of several differentially expressed transcripts, among which the SNGH6 deregulated lncRNA might be relevant in the pathogenesis and prognosis of pPCL with t(11;14). Overall, our data suggest that MMs and pPCLs with t(11;14) might be responsive to venetoclax based on different molecular programs, prompting further studies to elucidate better novel potential predictive biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma (MM) is the second most common haematologic malignancy, and it remains an incurable disease despite the advances of novel therapies. It is characterised by a multistep process that arises from a pre-malignant asymptomatic status-defined monoclonal gammopathy of undetermined significance (MGUS), evolves to a middle stage named smouldering myeloma phase (SMM), and culminates in the active disease (MM). Identification of early and non-invasive markers of the disease progression is currently an active field of investigation. In this review, we discuss the role and significance of microRNAs (miRNAs) as potential diagnostic biomarkers to predict the clinical transition from MGUS/SMM status to MM. Multiple myeloma (MM) is a hematological malignancy characterised by proliferation of clonal plasma cells (PCs) within the bone marrow (BM). Myelomagenesis is a multi-step process which goes from an asymptomatic phase, defined as monoclonal gammopathy of undetermined significance (MGUS), to a smouldering myeloma (SMM) stage, to a final active MM disease, characterised by hypercalcemia, renal failure, bone lesions anemia, and higher risk of infections. Overall, microRNAs (miRNAs) have shown to significantly impact on MM tumorigenesis, as a result of miRNA-dependent modulation of genes involved in pathways known to be crucial for MM pathogenesis and disease progression. We aim to revise the literature related to the role of miRNAs as potential diagnostic and prognostic biomarkers, thus highlighting their key role as novel players within the field of MM and related premalignant conditions. [ABSTRACT FROM AUTHOR]

Simple Summary: The growing interest in immunotherapy for the treatment of multiple myeloma demands a deep knowledge of the complex interactions between malignant and immune cells within the bone marrow. Indeed, understanding the cellular and molecular mechanisms underlying this network should represent the basis for the design of novel patient-oriented biological therapeutic approaches. Here, we describe the role of the main immune components of the myeloma niche along disease evolution and their implication in impairing/improving the response to anti-cancer treatments. Additionally, we provided an overview of the potential weakness of this pro-tumor interplay, evidencing novel therapeutic opportunities, which deserve future clinical investigations. Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as "smoldering" MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant "epigenetic" alterations of different normal cell populations within the bone marrow (BM) niche, including the "evasion" from immune-system control. Additionally, MM cells could "educate" the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients' worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients. [ABSTRACT FROM AUTHOR]

Simple Summary: A subset of colorectal cancers (CRCs) is characterized by a mismatch repair deficiency that is frequently associated with microsatellite instability (MSI). The compromised DNA repair machinery leads to the accumulation of tumor neoantigens affecting the sensitivity of MSI metastatic CRC to immune checkpoint inhibitors (CPIs), both upfront and in later lines of treatment. However, up to 30% of MSI CRCs exhibit primary resistance to frontline immune based therapy, and an additional subset develops acquired resistance. Here, we first discuss the clinical and molecular features of MSI CRCs and then we review how the loss of antigenicity, immunogenicity, and a hostile tumor microenvironment could influence primary and acquired resistance to CPIs. Finally, we describe strategies to improve the outcome of MSI CRC patients upon CPI treatment. Immune checkpoint inhibitors (CPIs) represent an effective therapeutic strategy for several different types of solid tumors and are remarkably effective in mismatch repair deficient (MMRd) tumors, including colorectal cancer (CRC). The prevalent view is that the elevated and dynamic neoantigen burden associated with the mutator phenotype of MMRd fosters enhanced immune surveillance of these cancers. In addition, recent findings suggest that MMRd tumors have increased cytosolic DNA, which triggers the cGAS STING pathway, leading to interferon-mediated immune response. Unfortunately, approximately 30% of MMRd CRC exhibit primary resistance to CPIs, while a substantial fraction of tumors acquires resistance after an initial benefit. Profiling of clinical samples and preclinical studies suggests that alterations in the Wnt and the JAK-STAT signaling pathways are associated with refractoriness to CPIs. Intriguingly, mutations in the antigen presentation machinery, such as loss of MHC or Beta-2 microglobulin (B2M), are implicated in initial immune evasion but do not impair response to CPIs. In this review, we outline how understanding the mechanistic basis of immune evasion and CPI resistance in MMRd CRC provides the rationale for innovative strategies to increase the subset of patients benefiting from CPIs. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is a cancer of immunoglobulin-secreting cells that accumulate in the bone marrow. Mesenchymal stromal cells are important components of the bone marrow microenvironment interacting with myeloma cells and having a pivotal role in the progression of the disease. Here we first review studies that have highlighted structural and functional differences between mesenchymal stromal cells derived from healthy donors and myeloma patients, and propose a model for the transition from the normal to the myeloma-condition of these cells. Next, we underscore the contribution of mesenchymal stromal cells to the promotion of myeloma growth and survival, development of drug resistance, dissemination and homing, myeloma bone disease, and the establishment of a pro-inflammatory and immunosuppressive microenvironment. It appears as if as a result of myeloma-mesenchymal stromal cell cross-talk, mesenchymal stromal cells in myeloma patients have converted into active contributors to the pathophysiology of the disease. Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment. [ABSTRACT FROM AUTHOR]

Simple Summary: The incidence and prevalence of endometrial cancer is increasing globally. The main factors involved in this increase have been the way women live today and what they eat and drink. In fact, the obesity pandemic that is sweeping across the planet is considered to be the main contributory feature. This review aims to introduce to a new audience, those that are not experts in the field, what is known about the different types of endometrial cancer and the mechanisms for their induction and protection. We also seek to summarise the existing knowledge on dietary and lifestyle factors that prevent endometrial development in susceptible populations and identify the main problem in this arena; the paucity of research studies and clinical trials that investigate the interaction(s) between diet, lifestyle and endometrial cancer risk whilst highlighting those areas of promise that should be further investigated. Endometrial cancer is the most common cancer affecting the reproductive organs of women living in higher-income countries. Apart from hormonal influences and genetic predisposition, obesity and metabolic syndrome are increasingly recognised as major factors in endometrial cancer risk, due to changes in lifestyle and diet, whereby high glycaemic index and lipid deposition are prevalent. This is especially true in countries where micronutrients, such as vitamins and minerals are exchanged for high calorific diets and a sedentary lifestyle. In this review, we will survey the currently known lifestyle factors, dietary requirements and hormonal changes that increase an individual's risk for endometrial cancer and discuss their relevance for clinical management. We also examine the evidence that everyday factors and clinical interventions have on reducing that risk, such that informed healthy choices can be made. In this narrative review, we thus summarise the dietary and lifestyle factors that promote and prevent the incidence of endometrial cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Genomic instability (GI) plays an important role in the pathobiology of multiple myeloma (MM) by promoting the acquisition of several tumor hallmarks. Molecular determinants of GI in MM are continuously emerging and will be herein discussed, with specific regard to non-coding RNAs. Targeting non-coding RNA molecules known to be involved in GI indeed provides novel routes to dampen such oncogenic mechanisms in MM. Multiple myeloma (MM) is a complex hematological malignancy characterized by abnormal proliferation of malignant plasma cells (PCs) within a permissive bone marrow microenvironment. The pathogenesis of MM is unequivocally linked to the acquisition of genomic instability (GI), which indicates the tendency of tumor cells to accumulate a wide repertoire of genetic alterations. Such alterations can even be detected at the premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) and, overall, contribute to the acquisition of the malignant traits underlying disease progression. The molecular basis of GI remains unclear, with replication stress and deregulation of DNA damage repair pathways representing the most documented mechanisms. The discovery that non-coding RNA molecules are deeply dysregulated in MM and can target pivotal components of GI pathways has introduced a further layer of complexity to the GI scenario in this disease. In this review, we will summarize available information on the molecular determinants of GI in MM, focusing on the role of non-coding RNAs as novel means to tackle GI for therapeutic intervention. [ABSTRACT FROM AUTHOR]

Simple Summary: The epithelial to mesenchymal transition (EMT) is a well-documented process in the study of cancer metastases. The cytoskeleton is an intricate network involved in various cellular activities and impacts cell shape, division, trafficking, and motility. However, several functions and activities of the cytoskeleton, which plays a pivotal role in EMT, are not fully understood. This review aims to provide significant insights into the cytoskeleton's physiological functions and the crucial role in the EMT process. Our review focuses on the participation of actin filaments, intermediate filaments, and microtubules in promoting EMT and their influence on cancer metastasis. We have also highlighted potential therapeutic targets associated with EMT activation for clinical intervention. A better understanding of multi-drug resistance (MDR) mechanisms in cancer cells with the cytoskeleton could accelerate the discovery of new therapies for aggressive cancer. In cancer cells, a vital cellular process during metastasis is the transformation of epithelial cells towards motile mesenchymal cells called the epithelial to mesenchymal transition (EMT). The cytoskeleton is an active network of three intracellular filaments: actin cytoskeleton, microtubules, and intermediate filaments. These filaments play a central role in the structural design and cell behavior and are necessary for EMT. During EMT, epithelial cells undergo a cellular transformation as manifested by cell elongation, migration, and invasion, coordinated by actin cytoskeleton reorganization. The actin cytoskeleton is an extremely dynamic structure, controlled by a balance of assembly and disassembly of actin filaments. Actin-binding proteins regulate the process of actin polymerization and depolymerization. Microtubule reorganization also plays an important role in cell migration and polarization. Intermediate filaments are rearranged, switching to a vimentin-rich network, and this protein is used as a marker for a mesenchymal cell. Hence, targeting EMT by regulating the activities of their key components may be a potential solution to metastasis. This review summarizes the research done on the physiological functions of the cytoskeleton, its role in the EMT process, and its effect on multidrug-resistant (MDR) cancer cells—highlight some future perspectives in cancer therapy by targeting cytoskeleton. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer onset and progression are promoted by high deregulation of the immune system. Recently, major advances in molecular and clinical cancer immunology have been achieved, offering new agents for the treatment of common tumors, often with astonishing benefits in terms of prolonged survival and even cure. Unfortunately, most tumors are still resistant to current immune therapy approaches, and basic knowledge of the resistance mechanisms is eagerly awaited. We focused our attention on noncoding RNAs, a class of RNA that regulates many biological processes by targeting selectively crucial molecular pathways and that, recently, had their role in cancer cell immune escape and modulation of the tumor microenvironment identified, suggesting their function as promising immunotherapeutic targets. In this scenario, we point out that noncoding RNAs are progressively emerging as immunoregulators, and we depict the current information on the complex network involving the immune system and noncoding RNAs and the promising therapeutic options under investigation. Novel opportunities are emerging from noncoding-RNAs for the treatment of immune-refractory tumors. Immunotherapy is presently one of the most promising areas of investigation and development for the treatment of cancer. While immune checkpoint-blocking monoclonal antibodies and chimeric antigen receptor (CAR) T-cell-based therapy have recently provided in some cases valuable therapeutic options, the goal of cure has not yet been achieved for most malignancies and more efforts are urgently needed. Noncoding RNAs (ncRNA), including microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), regulate several biological processes via selective targeting of crucial molecular signaling pathways. Recently, the key roles of miRNA and lncRNAs as regulators of the immune-response in cancer have progressively emerged, since they may act (i) by shaping the intrinsic tumor cell and microenvironment (TME) properties; (ii) by regulating angiogenesis, immune-escape, epithelial-to-mesenchymal transition, invasion, and drug resistance; and (iii) by acting as potential biomarkers for prognostic assessment and prediction of response to immunotherapy. In this review, we provide an overview on the role of ncRNAs in modulating the immune response and the TME. We discuss the potential use of ncRNAs as potential biomarkers or as targets for development or clinical translation of new therapeutics. Finally, we discuss the potential combinatory approaches based on ncRNA targeting agents and tumor immune-checkpoint inhibitor antibodies or CAR-T for the experimental treatment of human cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Bone metastases cause substantial morbidity and implicate worse clinical outcomes for clear-cell renal cell carcinoma patients. MicroRNAs are small RNA molecules that modulate gene translation and are involved in the development of cancer and metastasis. We identified six microRNAs that are potentially specifically involved in metastasis to bone, of which two seem protective and four implicate a higher risk. This aids further understanding of the process of metastasizing to bone. Furthermore, these microRNA hold potential for biomarkers or therapeutic targets. Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, the history of RNA interference discovery and current knowledge about microRNA biogenesis and post-transcriptional regulation of gene expression is summarized, with a special focus on microRNA clusters and families. Further, strong interplay between microRNAs and basic epigenetic mechanisms, such as DNA methylation and histone modifications, are introduced and associated with deregulated expression of microRNAs during tumor development. Finally, novel strategies for epigenetic-based therapies are discussed. MicroRNAs are small non-coding single-stranded RNA molecules regulating gene expression on a post-transcriptional level based on the seed sequence similarity. They are frequently clustered; thus, they are either simultaneously transcribed into a single polycistronic transcript or they may be transcribed independently. Importantly, microRNA families that contain the same seed region and thus target related signaling proteins, may be localized in one or more clusters, which are in a close relationship. MicroRNAs are involved in basic physiological processes, and their deregulation is associated with the origin of various pathologies, including solid tumors or hematologic malignancies. Recently, the interplay between the expression of microRNA clusters and families and epigenetic machinery was described, indicating aberrant DNA methylation or histone modifications as major mechanisms responsible for microRNA deregulation during cancerogenesis. In this review, the most studied microRNA clusters and families affected by hyper- or hypomethylation as well as by histone modifications are presented with the focus on particular mechanisms. Finally, the diagnostic and prognostic potential of microRNA clusters and families is discussed together with technologies currently used for epigenetic-based cancer therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer cells are consistently under oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. This feature has been exploited to develop therapeutic strategies that control tumor growth by modulating the oxidative stress in tumor cells. This review provides an overview of recent advances in cancer therapies targeting tumor oxidative stress, and highlights the emerging evidence implicating the effectiveness of cancer immunotherapies in intensifying tumor oxidative stress. The promises and challenges of combining ROS-inducing agents with cancer immunotherapy are also discussed. It has been well-established that cancer cells are under constant oxidative stress, as reflected by elevated basal level of reactive oxygen species (ROS), due to increased metabolism driven by aberrant cell growth. Cancer cells can adapt to maintain redox homeostasis through a variety of mechanisms. The prevalent perception about ROS is that they are one of the key drivers promoting tumor initiation, progression, metastasis, and drug resistance. Based on this notion, numerous antioxidants that aim to mitigate tumor oxidative stress have been tested for cancer prevention or treatment, although the effectiveness of this strategy has yet to be established. In recent years, it has been increasingly appreciated that ROS have a complex, multifaceted role in the tumor microenvironment (TME), and that tumor redox can be targeted to amplify oxidative stress inside the tumor to cause tumor destruction. Accumulating evidence indicates that cancer immunotherapies can alter tumor redox to intensify tumor oxidative stress, resulting in ROS-dependent tumor rejection. Herein we review the recent progresses regarding the impact of ROS on cancer cells and various immune cells in the TME, and discuss the emerging ROS-modulating strategies that can be used in combination with cancer immunotherapies to achieve enhanced antitumor effects. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is associated with metabolic changes related to increased cell proliferation and growth. These cancer-related metabolic features are largely dictated by specific oncogenes that are activated by chromosomal aberrations and epigenetic alterations in cancer cells. Multiple myeloma is an incurable plasma cell malignancy, which is characterized by recurrent chromosomal aberrations that drive the expression of established oncogenes such as MYC, Cyclin D1, FGFR3/MMSET and MAF/MAFB. In this review, we discuss the specific metabolic features of multiple myeloma plasma cells, and focus on the metabolic consequences of recurrent chromosomal aberrations, thereby providing an outline for the metabolic alterations that characterize multiple myeloma. Oncogene activation and malignant transformation exerts energetic, biosynthetic and redox demands on cancer cells due to increased proliferation, cell growth and tumor microenvironment adaptation. As such, altered metabolism is a hallmark of cancer, which is characterized by the reprogramming of multiple metabolic pathways. Multiple myeloma (MM) is a genetically heterogeneous disease that arises from terminally differentiated B cells. MM is characterized by reciprocal chromosomal translocations that often involve the immunoglobulin loci and a restricted set of partner loci, and complex chromosomal rearrangements that are associated with disease progression. Recurrent chromosomal aberrations in MM result in the aberrant expression of MYC, cyclin D1, FGFR3/MMSET and MAF/MAFB. In recent years, the intricate mechanisms that drive cancer cell metabolism and the many metabolic functions of the aforementioned MM-associated oncogenes have been investigated. Here, we discuss the metabolic consequences of recurrent chromosomal translocations in MM and provide a framework for the identification of metabolic changes that characterize MM cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Pediatric acute lymphoblastic leukemia (ALL) is the most prevalent cancer affecting children in developed societies. Here, we review the role of diet in control of the incidence and progression of childhood ALL. Prenatally, ALL risk is associated with higher birthweights of newborns, suggesting that ALL begins to evolve in-utero. Indeed, maternal diet influences the fetal genome and immune development. Postnatally, breastfeeding associates with decreased risk of ALL development. Finally, for the ALL-affected child, certain dietary regimens that impact the hormonal environment may impede disease progression. Improved understanding of the dietary regulation of hormones and immunity may inform better approaches to predict, protect, and ultimately save children afflicted with pediatric leukemia. Pediatric leukemias are the most prevalent cancers affecting children in developed societies, with childhood acute lymphoblastic leukemia (ALL) being the most common subtype. As diet is a likely modulator of many diseases, this review focuses on the potential for diet to influence the incidence and progression of childhood ALL. In particular, the potential effect of diets on genome stability and immunity during the prenatal and postnatal stages of early childhood development are discussed. Maternal diet plays an integral role in shaping the bodily composition of the newborn, and thus may influence fetal genome stability and immune system development. Indeed, higher birth weights of newborns are associated with increased risk of ALL, which suggests in-utero biology may shape the evolution of preleukemic clones. Postnatally, the ingestion of maternal breastmilk both nourishes the infant, and provides essential components that strengthen and educate the developing immune system. Consistently, breast-feeding associates with decreased risk of ALL development. For children already suffering from ALL, certain dietary regimens have been proposed. These regimens, which have been validated in both animals and humans, alter the internal hormonal environment. Thus, hormonal regulation by diet may shape childhood metabolism and immunity in a manner that is detrimental to the evolution or expansion of preleukemic and leukemic ALL clones. [ABSTRACT FROM AUTHOR]

Simple Summary: The BRAFV600E mutation accounts for 8–10% of metastatic colorectal cancer (mCRC) patients and it is an established prognostic factor. Median overall survival of this subset of patients is indeed so poor that it is similar to first line PFS of patients without this molecular alteration. An exception is represented by patients displaying concomitant MSI-H status who can benefit from immunotherapy with checkpoint inhibitors (CPIs). Recently, a targeted therapy with the combination of encorafenib and cetuximab provided for the first time a survival gain and thus translation in the clinic, even though acquired resistance limits the possibility of more than an incremental benefit. Many studies exploiting other different strategies are ongoing. In this review we present current therapies specifically headed to BRAFV600E mutant mCRC and systematically review ongoing clinical trials identifying different approaches under investigations: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. The BRAFV600E mutation is found in 8–10% of metastatic colorectal cancer (mCRC) patients and it is recognized as a poor prognostic factor with a median overall survival inferior to 20 months. At present, besides immune checkpoint inhibitors (CPIs) for those tumors with concomitant MSI-H status, recommended treatment options include cytotoxic chemotherapy + anti-VEGF in the first line setting, and a combination of EGFR and a BRAF inhibitor (cetuximab plus encorafenib) in second line. However, even with the latter targeted approach, acquired resistance limits the possibility of more than an incremental benefit and survival is still dismal. In this review, we discuss current treatment options for this subset of patients and perform a systematic review of ongoing clinical trials. Overall, we identified six emerging strategies: targeting MAPK pathway (monotherapy or combinations), targeting MAPK pathway combined with cytotoxic agents, intensive cytotoxic regimen combinations, targeted agents combined with CPIs, oxidative stress induction, and cytotoxic agents combined with antiangiogenic drugs and CPIs. In the future, the integration of new therapeutic strategies targeting key players in the BRAFV600E oncogenic pathways with current treatment approach based on cytotoxic chemotherapy and surgery is likely to redefine the treatment landscape of these CRC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple Myeloma (MM) is a blood cancer characterized by an uncontrolled growth of cells named plasma cells, within the bone marrow. Patients with MM may present with anemia, bone lesions and kidney impairment. Several studies have been performed in order to provide an explanation to how this tumor may develop. Among them, the so called "epigenetic modifications" certainly represent important players that have been shown to support MM development and disease progression. The present article aims to summarize the current knowledge in the specific are of "epigenetics" in MM. Multiple myeloma (MM) is a plasma cell dyscrasia characterized by proliferation of clonal plasma cells within the bone marrow. Several advances in defining key processes responsible for MM pathogenesis and disease progression have been made; and dysregulation of epigenetics, including DNA methylation and histone modification, has emerged as a crucial regulator of MM pathogenesis. In the present review article, we will focus on the role of epigenetic modifications within the specific context of MM. [ABSTRACT FROM AUTHOR]

Melanoma patients harboring the BRAFV600E mutation are treated with vemurafenib. Almost all of them ultimately acquire resistance, leading to disease progression. Here, we find that a small molecule from a marine sponge, panicein A hydroquinone (PAH), overcomes resistance of BRAFV600E melanoma cells to vemurafenib, leading to tumor elimination in corresponding human xenograft models in mice. We report the synthesis of PAH and demonstrate that this compound inhibits the drug efflux activity of the Hedgehog receptor, Patched. Our SAR study allowed identifying a key pharmacophore responsible for this activity. We showed that Patched is strongly expressed in metastatic samples from a cohort of melanoma patients and is correlated with decreased overall survival. Patched is a multidrug transporter that uses the proton motive force to efflux drugs. This makes its function specific to cancer cells, thereby avoiding toxicity issues that are commonly observed with inhibitors of ABC multidrug transporters. Our data provide strong evidence that PAH is a highly promising lead for the treatment of vemurafenib resistant BRAFV600E melanoma. [ABSTRACT FROM AUTHOR]

The biological impact of long non-coding RNAs (lncRNAs) in multiple myeloma (MM) is becoming an important aspect of investigation, which may contribute to the understanding of the complex pathobiology of the disease whilst also providing novel potential therapeutic targets. Herein, we investigated the expression pattern and the biological significance of the lncRNA ST3 beta-galactoside alpha-2,3 sialyltransferase 6 antisense RNA 1 (ST3GAL6-AS1) in MM. We documented a high ST3GAL6-AS1 expression level in MM compared to normal plasma cells (PCs) or other hematological malignancies. Transcriptome analyses of MM PCs from patients included in the CoMMpass database indicated a potential involvement of ST3GAL6-AS1 in MAPK signaling and ubiquitin-mediated proteolysis pathways. ST3GAL6-AS1 silencing by LNA-gapmeR antisense oligonucleotides inhibits cell proliferation and triggers apoptosis in MM cell line. Notably, ST3GAL6-AS1 silencing in vitro displayed the down-regulation of the MAPK pathway and protein ubiquitination. These data suggest that ST3GAL6-AS1 deregulation may play a pathogenetic role in MM by affecting both proliferation pathways and circuits fundamental for PC survival. However, ST3GAL6-AS1 expression levels seem not to be significantly associated with clinical outcome and its targeting appears to exert antagonistic effects with proteasome inhibitors used in MM. These findings strongly urge the need for further studies investigating the relevance of ST3GAL6-AS1 in MM. [ABSTRACT FROM AUTHOR]

Despite substantial advancements have been done in the understanding of the pathogenesis of plasma cell (PC) disorders, these malignancies remain hard-to-treat. The discovery and subsequent characterization of non-coding transcripts, which include several members with diverse length and mode of action, has unraveled novel mechanisms of gene expression regulation often malfunctioning in cancer. Increasing evidence indicates that such non-coding molecules also feature in the pathobiology of PC dyscrasias, where they are endowed with strong therapeutic and/or prognostic potential. In this review, we aim to summarize the most relevant findings on the biological and clinical features of the non-coding RNA landscape of malignant PCs, with major focus on multiple myeloma. The most relevant classes of non-coding RNAs will be examined, along with the mechanisms accounting for their dysregulation and the recent strategies used for their targeting in PC dyscrasias. It is hoped these insights may lead to clinical applications of non-coding RNA molecules as biomarkers or therapeutic targets/agents in the near future. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a deadly disease and therapeutic efficacy in advanced HCC is limited. Since progression of chronic liver disease to HCC involves a long latency period of a few decades, a significant window of therapeutic opportunities exists for prevention of HCC and improve patient prognosis. Nonetheless, there has been no clinical advancement in instituting HCC chemopreventive strategies. Some of the major challenges are heterogenous genetic aberrations of HCC, significant modulation of tumor microenvironment and incomplete understanding of HCC tumorigenesis. To this end, animal models of HCC are valuable tools to evaluate biology of tumor initiation and progression with specific insight into molecular and genetic mechanisms involved. In this review, we describe various animal models of HCC that facilitate effective ways to study therapeutic prevention strategies that have translational potential to be evaluated in a clinical context. [ABSTRACT FROM AUTHOR]

Recently, attention has been drawn to the role of non-coding regions of the genome in cancer pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs with 19–25 bases of length that control gene expression by destroying messenger RNA or inhibiting its translation. In multiple myeloma (MM), the expression of several miRNAs, such as miR-15a and miR-16, is markedly decreased and their target genes upregulated, suggesting their role as tumor-suppressing miRNAs. In contrast, miRNAs such as miR-21 and miR-221 are highly expressed and function as oncogenes (oncomiRs). In addition, several miRNAs, such as those belonging to the miR-34 family, are transcriptional targets of p53 and mediate its tumor-suppressive functions. Many miRNAs are associated with drug resistance, and the modulation of their expression or activity might be explored to reverse it. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. miRNA regulation mechanisms have not been fully elucidated. Many miRNAs are epigenetically controlled by DNA methylation and histone modification, and others regulate the expression of epigenetic modifiers, indicating that miRNA and other epigenetic effectors are part of a network. In this review, we outlined the roles of miRNAs in MM and their potential to predict MM prognosis and develop novel therapies. [ABSTRACT FROM AUTHOR]

Olive oil contains different biologically active polyphenols, among which oleacein, the most abundant secoiridoid, has recently emerged for its beneficial properties in various disease contexts. By using in vitro models of human multiple myeloma (MM), we here investigated the anti-tumor potential of oleacein and the underlying bio-molecular sequelae. Within a low micromolar range, oleacein reduced the viability of MM primary samples and cell lines even in the presence of bone marrow stromal cells (BMSCs), while sparing healthy peripheral blood mononuclear cells. We also demonstrated that oleacein inhibited MM cell clonogenicity, prompted cell cycle blockade and triggered apoptosis. We evaluated the epigenetic impact of oleacein on MM cells, and observed dose-dependent accumulation of both acetylated histones and α-tubulin, along with down-regulation of several class I/II histone deacetylases (HDACs) both at the mRNA and protein level, providing evidence of the HDAC inhibitory activity of this compound; conversely, no effect on global DNA methylation was found. Mechanistically, HDACs inhibition by oleacein was associated with down-regulation of Sp1, the major transactivator of HDACs promoter, via Caspase 8 activation. Of potential translational significance, oleacein synergistically enhanced the in vitro anti-MM activity of the proteasome inhibitor carfilzomib. Altogether, these results indicate that oleacein is endowed with HDAC inhibitory properties, which associate with significant anti-MM activity both as single agent or in combination with carfilzomib. These findings may pave the way to novel potential anti-MM epi-therapeutic approaches based on natural agents. [ABSTRACT FROM AUTHOR]

Aberrant expression of microRNAs (miRNAs) has been associated to the pathogenesis of multiple myeloma (MM). While miR-155 is considered a therapeutic target in several malignancies, its role in MM is still unclear. The analysis of miR-155 expression indicates its down-regulation in MM patient-derived as compared to healthy plasma cells, thus pointing to a tumor suppressor role in this malignancy. On this finding, we investigated miR-155 replacement as a potential anti-tumor strategy in MM. The miR-155 enforced expression triggered anti-proliferative and pro-apoptotic effects in vitro. Given the lower miR-155 levels in bortezomib-resistant as compared to sensitive MM cells, we analyzed the possible involvement of miR-155 in bortezomib resistance. Importantly, miR-155 replacement enhanced bortezomib anti-tumor activity both in vitro and in vivo in a xenograft model of human MM. In primary MM cells, we observed an inverse correlation between miR-155 and the mRNA encoding the proteasome subunit gene PSMβ5, whose dysregulation has been largely implicated in bortezomib resistance, and we validated PSMβ5 3′UTR mRNA targeting, along with reduced proteasome activity, by miR-155. Collectively, our findings demonstrate that miR-155 elicits anti-MM activity, likely via proteasome inhibition, providing the framework for miR-155-based anti-MM therapeutic strategies. [ABSTRACT FROM AUTHOR]