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Topic Review
3D Modeling of Epithelial Tumors
The current statistics on cancer show that 90% of all human cancers originate from epithelial cells. Breast and prostate cancer are examples of common tumors of epithelial origin that would benefit from improved drug treatment strategies. About 90% of preclinically approved drugs fail in clinical trials, partially due to the use of too simplified in vitro models and a lack of mimicking the tumor microenvironment in drug efficacy testing. This entry focuses on the epithelial cancers, followed by experimental models designed to recapitulate the epithelial tumor structure and microenvironment. A specific focus is to put on novel technologies for cell culture of spheroids, organoids, and 3D-printed tissue-like models, utilizing biomaterials of natural or synthetic origins, and how the models could be utilized for nanotechnology-based drug delivery in the future.
  • 1.2K
  • 24 Jun 2021
Topic Review
Pterostilbene in Cancer Therapy
Natural polyphenols are organic chemicals which contain phenol units in their structures and possess antitumor properties. However, a key problem is their short half-life and low bioavailability under in vivo conditions. Pterostilbene (3,5-dimethoxy-4'-hydroxystilbene; PT) is a phytoalexin originally isolated from the heartwood of red sandalwood. As recently reported by our group, PT was shown to be effective in the treatment of melanoma. Counterintuitively, PT is not effective (cytotoxic) against melanoma in vitro, and only under in vivo conditions does PT display its anticancer activity. This study elucidated that PT can be effective against melanoma through the inhibition of adrenocorticotropic hormone production in the brain of a mouse, which weakens the Nrf2-dependent antioxidant defenses of melanoma and also pancreatic cancers. This results in both the inhibition of tumor growth and sensitization of the tumor to oxidative stress. Moreover, PT can promote cancer cell death via a mechanism involving lysosomal membrane permeabilization. Different grades of susceptibility were observed among the different cancer cells depending on their lysosomal heat shock protein 70 content, a known stabilizer of lysosomal membranes. In addition, the safety of PT administered i.v. has been evaluated in mice. PT was found to be pharmacologically safe because it showed no organ-specific or systemic toxicity (including tissue histopathologic examination and regular hematology and clinical chemistry data) even when administered i.v. at a high dose (30 mg/kg per day × 23 days). Moreover, new pharmacological advances are being developed to increase its bioavailability and, thereby, its bioefficacy. Therefore, although applications of PT in cancer therapy are just beginning to be explored, it represents a potential (and effective) adjuvant/sensitizing therapy which may improve the results of various oncotherapies. The aim of this review is to present and discuss the results that in our opinion best support the usefulness of PT in cancer therapy, making special emphasis on the in vivo evidence.
  • 1.2K
  • 26 Jul 2021
Topic Review
Connexins and Integrins in Exosomes
Connexins and integrins, the two structurally and functionally distinct families of transmembrane proteins, have been shown to be inter-connected by various modes of cross-talk in cells, such as direct physical coupling via lateral contact, indirect physical coupling via actin and actin-binding proteins, and functional coupling via signaling cascades.
  • 1.2K
  • 11 Oct 2021
Topic Review
Oncogenic Tyrosine Phosphatases
Despite a large number of therapeutic options available, malignant melanoma remains a highly fatal disease, especially in its metastatic forms. The oncogenic role of protein tyrosine phosphatases (PTPs) is becoming increasingly clear, paving the way for novel antitumor treatments based on their inhibition. In this review, we present the oncogenic PTPs contributing to melanoma progression and we provide, where available, a description of new inhibitory strategies designed against these enzymes and possibly useful in melanoma treatment. Considering the relevance of the immune infiltrate in supporting melanoma progression, we also focus on the role of PTPs in modulating immune cell activity, identifying interesting therapeutic options that may support the currently applied immunomodulating approaches.
  • 1.2K
  • 13 Oct 2020
Topic Review
The KEAP1–NRF2 System
The Kelch-like ECH-associated protein (KEAP1)– Nuclear factor erythroid-derived 2-like 2 (encoded by the Nfe2l2 gene; NRF2) system attracts extensive interest from scientists in basic and clinical cancer research fields, as NRF2 exhibits activity as both an oncogene and tumor suppressor, depending on the context. Especially unique and malignant, NRF2-addicted cancers exhibit high levels of NRF2 expression. Somatic mutations identified in the NRF2 or KEAP1 genes of NRF2-addicted cancers cause the stabilization and accumulation of NRF2. NRF2-addicted cancers hijack the intrinsic roles that NRF2 plays in cytoprotection, including antioxidative and anti-electrophilic responses, as well as metabolic reprogramming, and acquire a marked advantage to survive under severe and limited microenvironments. Therefore, NRF2 inhibitors are expected to have therapeutic effects in patients with NRF2-addicted cancers. In contrast, NRF2 activation in host immune cells exerts significant suppression of cancer cell growth, indicating that NRF2 inducers also have the potential to be therapeutics for cancers. Thus, the KEAP1–NRF2 system makes a broad range of contributions to both cancer development and suppression. These observations thus demonstrate that both NRF2 inhibitors and inducers are useful for the treatment of cancers with high NRF2 activity.
  • 1.2K
  • 12 Jan 2021
Topic Review
Targeted Agents and Immunotherapy in Sinonasal Cancers
Sinonasal cancers (SNCs) include different tumors of the nasal cavities, maxillary, sphenoidal, ethmoidal, and frontal sinuses. Epithelial SNCs include different histological subtypes: the most common is squamous cell carcinoma (SCC), either keratinizing or non-keratinizing, followed by adenocarcinoma (intestinal-type or non-intestinal type), sinonasal undifferentiated carcinoma (SNUC), sinonasal neuroendocrine carcinoma (SNEC), NUT carcinoma, lymphoepithelial carcinoma, teratocarcinosarcoma, and minor salivary gland tumors.
  • 1.2K
  • 23 Dec 2022
Topic Review
Genetic Alterations Featuring Biological Models
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related death worldwide. This high mortality rate is due to the disease’s lack of symptoms, resulting in a late diagnosis. Biomarkers and treatment options for pancreatic cancer are also limited. In order to overcome this, new research models and novel approaches to discovering PDAC biomarkers are required. In this review, we outline the hereditary and somatic causes of PDAC and provide an overview of the recent genome wide association studies (GWAS) and pathway analysis studies. We also provide a summary of some of the systems used to study PDAC, including established and primary cell lines, patient-derived xenografts (PDX), and newer models such as organoids and organ-on-chip. These ex vitro laboratory systems allow for critical research into the development and progression of PDAC.
  • 1.2K
  • 16 Oct 2020
Topic Review
Androgen Receptor in Lung Cancer
The androgen receptor (AR) is expressed in many cell types, and its related signaling is widely investigated in hormone-dependent cancers such as prostate and breast. The significance of the AR, however, has been detected even in other cancers, including gastric, bladder, kidney, lung, hepatic, and pancreatic, in which growth and spreading are not strictly or notoriously dependent on sex steroid hormone action. 
  • 1.2K
  • 15 Jun 2023
Topic Review
Recurrent Glioblastoma
Glioblastoma (GBM) is the most aggressive central nervous system (CNS) primary malignancy in adults, with a median age at diagnosis of 65 years.
  • 1.2K
  • 08 Feb 2021
Topic Review
Belantamab Mafodotin and Multiple Myeloma
Multiple myeloma (MM) is a hematologic malignancy characterized by excessive clonal proliferation of plasma cells. The treatment of multiple myeloma presents a variety of unique challenges due to the complex molecular pathophysiology and incurable status of the disease at this time. Given that MM is the second most common blood cancer with a characteristic and unavoidable relapse/refractory state during the course of the disease, the development of new therapeutic modalities is crucial. Belantamab mafodotin (belamaf, GSK2857916) is a first-in-class therapeutic, indicated for patients who have previously attempted four other treatments, including an anti-CD38 monoclonal antibody, a proteosome inhibitor, and an immunomodulatory agent. In November 2017, the FDA designated belamaf as a breakthrough therapy for heavily pretreated patients with relapsed/refractory multiple myeloma. In August 2020, the FDA granted accelerated approval as a monotherapy for relapsed or treatment-refractory multiple myeloma. The drug was also approved in the EU for this indication in late August 2020. Of note, belamaf is associated with the following adverse events: decreased platelets, corneal disease, decreased or blurred vision, anemia, infusion-related reactions, pyrexia, and fetal risk, among others. Further studies are necessary to evaluate efficacy in comparison to other standard treatment modalities and as future drugs in this class are developed
  • 1.2K
  • 24 Feb 2021
Topic Review
Impacts of COVID-19
SARS-CoV-2, the causative agent of coronavirus disease 2019 (COVID-19), has caused widespread morbidity and mortality since its emergence. The COVID-19 pandemic has become widespread and known as a pathology of the respiratory system, affecting the ciliary epithelium at an early stage. In severe cases, COVID-19 can lead to development of lung disease: acute respiratory distress syndrome (ARDS). A variety of extrapulmonary symptoms may also occur, including acute renal failure (AKI); acute heart failure; coagulopathy; thromboembolic complications, including stroke and pulmonary embolism; and circulatory shock. The COVID-19 pandemic caused by the SARS-CoV-2 coronavirus remains a global public health concern due to the systemic nature of the infection and its long-term consequences, many of which remain to be elucidated. SARS-CoV-2 targets endothelial cells and blood vessels, altering the tissue microenvironment, its secretion, immune-cell subpopulations, the extracellular matrix, and the molecular composition and mechanical properties.
  • 1.2K
  • 05 Jun 2023
Topic Review
Anti-Cancer and Anti-Inflammatory Properties of Black Garlic
Black garlic (BG) is a fermented form of garlic (Allium sativum L.), produced at precisely defined temperatures, humidities, and time periods. Although garlic has been used for thousands of years, black garlic is a relatively new discovery. There are many bioactive compounds in black garlic that give it medicinal properties, including anti-inflammatory and anti-cancer properties.
  • 1.2K
  • 19 Feb 2024
Topic Review
Patient-Derived Cancer Organoids
The emergence of three-dimensional human organoids has opened the door for the development of patient-derived cancer organoid (PDO) models, which closely recapitulate parental tumor tissue. 
  • 1.2K
  • 01 Jun 2021
Topic Review
Malignant Transformation of Postmenopausal Endometriosis
Endometriosis is a disease that affects 6–10% of women of reproductive age. Although it is a benign condition, endometriotic lesions have around a 1% risk of malignant transformation. Since endometriosis is an estrogen-dependent disease, it can be expected to resolve or disappear in menopause. However, the prevalence of menopausal endometriosis is 2–4%. In these cases, the risk of malignant transformation is a rare but possible event. 
  • 1.2K
  • 16 Aug 2021
Topic Review
Fasting, Hormones, and Cancer Prevention
Hormonal and growth factor alterations, related to an elevated food consumption and excessive adiposity, affect the regulation of genes involved in cellular processes including proliferation, differentiation and DNA repair, allowing cells to survive and proliferate despite the accumulation of mutations which lead to malignant transformation. The growth hormone/insulin growth factor-1 (GH/IGF-1)/ insulin pathway and its downstream effectors, in fact, are known to promote aging and/or age-related diseases, including cancer, in many model organisms. The restriction of nutrients is established to have strong effects on levels of hormones and growth factors, delaying the incidence of age-related diseases and prolonging lifespan.
  • 1.2K
  • 28 Oct 2021
Topic Review
Representative Drivers for TB Development and p-EMT Induction
Tumor budding (TB), a microscopic finding in the stroma ahead of the invasive fronts of tumors, has been well investigated and reported as a prognostic marker in head and neck squamous cell carcinoma (HNSCC). Epithelial–mesenchymal transition (EMT) is a crucial step in tumor progression and metastasis, and its status cannot be distinguished from TB. The current understanding of partial EMT (p-EMT), the so-called halfway step of EMT, focuses on the tumor microenvironment (TME). Although this evidence has been investigated, the clinicopathological and biological relationship between TB and p-EMT remains debatable. At the invasion front, previous research suggested that cancer-associated fibroblasts (CAFs) are important for tumor progression, metastasis, p-EMT, and TB formation in the TME. 
  • 1.2K
  • 21 Feb 2023
Topic Review
PET for Microenvironment-Targeted Therapy
 Quantitative parameters of FDG-PET, such as SUV and TLG have been used to evaluate therapeutic response. Recent advancement in anti-cancer therapeutics showed that tumor response to molecular-targeted drugs and immune-checkpoint inhibitors is different from conventional chemotherapy in terms of temporal metabolic alteration and morphological change after the course of effective therapy. Metabolic changes and temporal enlargement due to immune cell infiltration seen after immune-checkpoint inhibitors, such as anti-programmed cell death-1 (PD-1) and anti-programmed cell death ligand 1 (PD-L1) antibodies facilitated the modification of conventional Response Evaluation Criteria in Solid Tumor and FDG-PET response evaluation criteria. Tumor microenvironment including cancer stem cells (CSCs) that is thought to be a root cause of tumor heterogeneity; is considered a target of novel and effective therapy.   Accumulation of FDG reflects glucose metabolism of both cancer cells and immunologically competent cells in the tumor microenvironment. Immunological reaction to the therapy differs among patients according to the individual immune function. Considering the heterogeneity of tumor tissue and individual variation in tumor response to immunotherapy, radiomics approach combines quantitative image features with deep learning algorithm have the potentials to improve response assessment in more personalized treatment.   Stromal cell-derived factor 1 (SDF-1)/C-X-C chemokine receptor type 4 (CXCR4)-targeted α-particle therapy has been introduced, because SDF-1/CXCR4 axis is known to increase epithelial-mesenchymal transition to facilitate invasion and metastasis, and regulate immune response by accelerating T cell proliferation as well as PD-1 and PD-L1 expression in cancer cells and cytotoxic T lymphocytes, respectively. Prominent energy profile and biological effect of α-particles are promising as an alternative in targeted radionuclide therapy (TRT). Radiation dosimetry according to the theranostics approach will permit accurate TRT and artificial intelligence-based treatment decision making and precise response evaluation would be a precision nuclear medicine in the future.
  • 1.2K
  • 09 Feb 2021
Topic Review
Oligometastatic Breast Cancer
Breast cancer (BC) is the most frequent cancer among women and represents the second leading cause of cancer-specific death. A subset of patients with metastatic breast cancer (MBC) presents limited disease, termed ‘oligometastatic’ breast cancer (OMBC). The oligometastatic disease can be managed with different treatment strategies to achieve long-term remission and eventually cure. Several approaches are possible to cure the oligometastatic disease: locoregional treatments of the primary tumor and of all the metastatic sites, such as surgery and radiotherapy; systemic treatment, including target-therapy or immunotherapy, according to the biological status of the primary tumor and/or of the metastases; or the combination of these approaches. Encouraging results involve local ablative options, but these trials are limited by being retrospective and affected by selection bias. Systemic therapy, e.g., the use of CDK4/6 inhibitors for hormone receptor-positive (HR+)/HER-2 negative BC, leads to an increase of progression-free survival (PFS) and overall survival (OS) in all the subgroups, with favorable toxicity. Regardless of the lack of substantial data, this subset of patients could be treated with curative intent; the appropriate candidates could be mostly young women, for whom a multidisciplinary aggressive approach appears suitable.
  • 1.2K
  • 25 Jun 2021
Topic Review
ICI-Based Combination Therapy for HCC
Advanced, unresectable hepatocellular carcinoma has a dismal outcome. Multiple immune checkpoint inhibitors (ICIs) targeting the programmed-cell death 1 pathway (PD-1/L1) have been approved for the treatment of advanced HCC. However, outcomes remain undesirable and unpredictable on a patient-to-patient basis. The combination of anti-PD-1/L1 with alternative agents, chiefly cytotoxic T-lymphocyte antigen-4 (CTLA-4) ICIs or agents targeting other oncogenic pathways such as the vascular endothelial growth factor (VEGF) pathway and the c-MET pathway, has, in addition to the benefit of directly targeting alterative oncogenic pathways, in vitro evidence of synergism through altering the genomic and function signatures of T cells and expression of immune checkpoints. Several trials have been completed or are underway evaluating such combinations. Finally, studies utilizing transcriptomics and organoids are underway to establish biomarkers to predict ICI response. 
  • 1.2K
  • 06 May 2021
Topic Review
Targeting Tryptophan Metabolism to Treat Cancers
Major hallmarks of cancers are connected to dysfunctions in many metabolic pathways aiming at providing the energetic needs and the raw material for cellular growth and the signaling molecules needed for oncogenesis. Tryptophan (TRP) catabolism through the kynurenine (KYN) pathway was reported to play immunosuppressive actions across many types of cancer. However, results from clinical trials assessing the benefit of inhibiting key limiting enzymes of this pathway such as indoleamine 2,3-dioxygenase (IDO1) or tryptophan 2,3-dioxygenase (TDO2) failed to meet the expectations. Bearing in mind the complexity of the tumoral terrain and the existence of different cancers with IDO1/TDO2 expressing and non-expressing tumoral cells, here we present a comprehensive analysis of the TRP global metabolic hub and the approach of inhibiting these pathways as a potential therapeutic option to treat cancers such as liver cancers. 
  • 1.2K
  • 29 Mar 2022
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