Simple Summary Stimulating our body's own immune response to fight cancer is important for the success of cancer treatment in general. To further improve current cancer therapy, preclinical... Show moreSimple Summary Stimulating our body's own immune response to fight cancer is important for the success of cancer treatment in general. To further improve current cancer therapy, preclinical research shows that short-term fasting diets enhance cancer therapy efficacy, such as chemotherapy. Short-term fasting diets are low-caloric and low in protein for 3-5 days; they are usually done every couple of weeks. This review summarizes preclinical and clinical evidence of fasting diets synergizing with cancer therapy by boosting antitumor immunity. Short-term fasting (STF), using a low caloric, low protein fasting mimicking diet (FMD), appears to be a promising strategy to enhance chemotherapy-based cancer efficacy, while potentially alleviating toxicity. Preclinical results suggest that enhanced tumor immunity and decreased growth signaling, via lowering of circulating insulin and insulin growth factor 1 (IGF-1) levels form the potential underlying mechanisms. STF may boost anti-tumor responses by promoting tumor immunogenicity and decreasing local immunosuppression. These findings warrant further studies focused on the combination of STF, not only with chemotherapy, but also with immunotherapy to evaluate the full range of benefits of STF in cancer treatment. Here, we delineate the underlying anticancer mechanisms of fasting. We summarize preclinical evidence of STF boosting antitumor immunity and alleviating immunosuppression, as well as the clinical findings reporting the immunomodulatory effects of STF during various cancer treatments, including immunotherapy. Show less
Simple Summary:& nbsp;Despite improvements in the treatment of several cancer types, the extremely poor prognosis of pancreatic cancer patients has remained unchanged over the last decades.... Show moreSimple Summary:& nbsp;Despite improvements in the treatment of several cancer types, the extremely poor prognosis of pancreatic cancer patients has remained unchanged over the last decades. Therefore, new therapeutic regimens for pancreatic cancer are highly needed. In this review, we will discuss the potential of induced pluripotent stem cells (iPSCs) to generate representative pancreatic cancer models that can aid the development of novel diagnostics and therapeutic strategies. Furthermore, the potential of iPSCs as pancreatic cancer vaccines or as a basis for cellular therapies will be discussed. With promising preclinical results and ongoing clinical trials, the potential of iPSCs to further the treatment of pancreatic cancer is being explored and, in turn, will hopefully provide additional therapies to increase the poor survival rates of this patient population.Advances in the treatment of pancreatic ductal adenocarcinoma (PDAC) using neoadjuvant chemoradiotherapy, chemotherapy, and immunotherapy have had minimal impact on the overall survival of patients. A general lack of immunogenic features and a complex tumor microenvironment (TME) are likely culprits for therapy refractoriness in PDAC. Induced pluripotent stem cells (iPSCs) should be explored as a means to advance the treatment options for PDAC, by providing representative in vitro models of pancreatic cancer development. In addition, iPSCs could be used for tailor-made cellular immunotherapies or as a source of tumor-associated antigens in the context of vaccination. Show less
Oncolytic viruses are promising agents for cancer therapy because they selectively infect and kill tumor cells, and because they trigger immune responses that can boost anticancer immunity. Key to... Show moreOncolytic viruses are promising agents for cancer therapy because they selectively infect and kill tumor cells, and because they trigger immune responses that can boost anticancer immunity. Key to the latter process is the production of type I interferons (IFN-Is) that can turn noninflamed "cold" tumors into "hot" ones. Besides this desired anticancer effect, IFN-Is are antiviral and successful oncolytic virotherapy thus relies on tightly controlled IFN-I levels. This requires a profound understanding of when and how tumor cells induce IFN-I in response to specific viruses. In this study, we uncovered two key factors that augment IFN-I production in transformed human myeloid cells infected with a tumor-selective reovirus. Viral replication and IFN-alpha/beta receptor (IFNAR) signaling progressively reinforced the levels of IFN-I expressed by infected cells. Mechanistically, both augmented the activation of interferon regulatory factor 3, a key transcription factor for IFN beta expression. Our findings imply that reovirus-permissive tumor cells themselves are a major source of IFN-I expression. As tumors can perturb the IFNAR pathway for their own survival, reovirus-exposed IFNAR-unresponsive tumors may need additional therapeutic intervention to promote the secretion of sufficient IFN-I into the tumor microenvironment. Our increased understanding of the parameters that affect reovirus-induced IFN-I levels could aid in the design of tailored virus-based cancer therapies. Show less
Metastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are... Show moreMetastasis is the leading cause of death for cancer patients. During cancer progression, the initial detachment of cells from the primary tumor and the later colonization of a secondary organ are characterized as limiting steps for metastasis. Epithelial-mesenchymal transition (EMT) and mesenchymal-epithelial transition (MET) are opposite dynamic multistep processes that enable these critical events in metastasis by altering the phenotype of cancer cells and improving their ability to migrate, invade and seed at distant organs. Among the molecular pathways that promote tumorigenesis in late-stage cancers, transforming growth factor-beta (TGF-beta) is described as an EMT master inducer by controlling different genes and proteins related to cytoskeleton assembly, cell-cell attachment and extracellular matrix remodeling. Still, despite the successful outcomes of different TGF-beta pharmacological inhibitors in cell culture (in vitro) and animal models (in vivo), results in cancer clinical trials are poor or inconsistent at least, highlighting the existence of crucial components in human cancers that have not been properly explored. Here we review most recent findings to provide perspectives bridging the gap between on-target anti-TGF-beta therapiesin vitroand in pre-clinical models and the poor clinical outcomes in treating cancer patients. Specifically, we focus on (i) the dual roles of TGF-beta signaling in cancer metastasis; (ii) dynamic signaling; (iii) functional differences of TGF-beta free in solution vs. in exosomes; (iv) the regulatory effects of tumor microenvironment (TME) - particularly by cancer-associated fibroblasts - on TGF-beta signaling pathway. Clearly identifying and establishing those missing links may provide strategies to revitalize and clinically improve the efficacy of TGF-beta targeted therapies. Show less
Transforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors.... Show moreTransforming growth factor (TGF)-beta is a secreted multifunctional cytokine that signals via plasma membrane TGF-beta type I and type II receptors and intercellular SMAD transcriptional effectors. Aberrant inter- and intracellular TGF-beta signaling can contribute to cancer progression. In normal cells and early stages of cancer, TGF-beta can stimulate epithelial growth arrest and elicit a tumor suppressor function. However, in late stages of cancer, when the cytostatic effects of TGF-beta in cancer cells are blocked, TGF-beta signaling can act as tumor promoter by its ability to stimulate epithelial-to-mesenchymal transition of cancer cells, by stimulating angiogenesis, and by promoting evasion of immune responses. In this review, we will discuss the rationale and challenges of targeting TGF-beta signaling in cancer and summarize the clinical status of TGF-beta signaling inhibitors that interfere with TGF-beta bioavailability, TGF-beta/receptor interaction, or TGF-beta receptor kinase function. Moreover, we will discuss targeting of TGF-beta signaling modulators and downstream effectors as well as alternative approaches by using promising technologies that may lead to entirely new classes of drugs. Show less
