Search Results (117)

Cancer-associated fibroblasts (CAFs) are critical components of the tumor microenvironment that promote cancer progression and immune evasion. Adipocyte enhancer-binding protein 1 gene (AEBP1), which encodes aortic carboxypeptidase-like protein (ACLP), has been implicated in tissue remodeling and fibrosis, yet its role in CAF biology across cancers remains poorly understood. Here, we performed a pan-cancer transcriptomic analysis using The Cancer Genome Atlas (TCGA) and found that AEBP1 expression strongly correlates with expression of collagen family genes in the majority of solid tumors. Integration of single-cell RNA-sequencing datasets from breast and pancreatic cancers revealed that AEBP1 is predominantly expressed in CAFs, where it is co-expressed with collagens and CAF marker genes. Functional experiments using three-dimensional (3D) spheroids composed of oral squamous cell carcinoma (OSCC)-derived CAFs showed that AEBP1 knockdown significantly reduced spheroid stiffness without altering their morphology or size, indicating that ACLP contributes to the mechanical properties of tumor tissues. Together with earlier findings linking AEBP1/ACLP to reduced CD8⁺ T-cell infiltration, our results suggest that stromal AEBP1/ACLP enhances both extracellular matrix stiffness and immune suppression and highlights AEBP1/ACLP as a potential therapeutic target through which to remodel the tumor microenvironment and improve anti-tumor immunity. Full article

P2Y₂ receptors are a subclass of G protein-coupled receptors activated by the extracellular nucleotides ATP and UTP. These receptors are widely expressed in multiple tissues—including the brain, lungs, heart, and kidneys—and play pivotal roles in inflammation, wound healing, and cell migration. Through coupling with various G proteins, P2Y₂ receptors initiate diverse intracellular signaling pathways that mediate calcium mobilization, cytokine release, and cytoskeletal reorganization. Recent studies highlight their dual roles in health and disease. In physiological contexts, P2Y₂ receptors contribute to immune modulation and tissue repair. In pathological conditions, they are implicated in Alzheimer’s disease by promoting non-amyloidogenic processing of amyloid precursor protein and in dry eye disease by enhancing mucin secretion while modulating ocular inflammation. They also influence chloride secretion and mucosal hydration in cystic fibrosis and contribute to inflammatory regulation and epithelial repair in inflammatory bowel disease. Additionally, P2Y₂ receptors modulate breast cancer progression by regulating cell adhesion, migration, and matrix remodeling. Their involvement in blood pressure regulation via epithelial sodium channel modulation and their facilitative role in HIV-1 entry further underscore their clinical significance. These multifaceted functions position P2Y₂ receptors as promising therapeutic targets for diverse diseases, warranting further investigation for translational applications. Full article

The tumor microenvironment (TME) comprises neoplastic and stromal cells, and extracellular matrix elements, all engaging in a complex interplay that ultimately dictates tumorigenesis, cancer progression, and therapeutic response. While extensive research on the TME has been conducted in human oncology, data on its veterinary counterpart, particularly in feline mammary tumors (FMTs), are still scarce. In this review, we explore current understanding of feline mammary carcinoma (FMC) microenvironment, focusing on tumor necrosis, fibrosis, angiogenesis, adipose tissue tumor-associated inflammation, extracellular vesicles, and epithelial–mesenchymal transition (EMT) and their prognostic implications. In FMC, remodeling of collagen fibers, cancer-associated fibroblasts (CAFs), regulatory T cells (Tregs) and elevated serum leptin have been associated with poor prognosis, whereas stromal cytotoxic T cells correlate with more favorable outcomes. By contrast, findings on necrosis and pro-angiogenic factors remain inconsistent, and research on extracellular vesicles (EVs) is still in its early stages. This review presents insights from human breast cancer (HBC) that further support and elucidate the potential relevance of these TME components. As FMCs are highly aggressive tumors, a deeper understanding of their microenvironment could not only improve prognostic accuracy but also uncover novel therapeutic targets. Furthermore, due to their similarities, FMCs offer a potential valuable spontaneous model for HBC, particularly for the aggressive triple-negative phenotypes. Full article

Background: Patients with systemic sclerosis have a significantly increased incidence of developing various solid malignancies within a few years of systemic sclerosis onset, but the mechanism of tumor promotion is not well understood. The tight skin (TSK) mouse has been a valuable model for investigating systemic sclerosis-related pathologies due to increased extracellular matrix deposition, fibrosis in connective tissues, and altered immune cell activation. Despite the role of extracellular matrix and fibrosis in cancer progression, the potential of the TSK mouse as a model for cancer studies is unexplored. Methods: To investigate the impact of the altered microenvironment in TSK mice on cancer progression, we compared the tumor-forming capabilities (by subcutaneous and intraperitoneal injection) in TSK mice and WT mice using syngeneic breast cancer, melanoma, and ovarian cancer cell lines. We used bulk and single-cell RNA sequencing to characterize these tumors and identify the changes in the TSK microenvironment that promote cancer formation. Results: In all three cancer types, TSK mice exhibited more invasive subcutaneous tumors in comparison to WT controls, underscoring the role of the TSK subcutaneous microenvironment in promoting cancer progression. Furthermore, the heightened invasiveness of ovarian tumors implanted intraperitoneally suggests that the peritoneal microenvironment in TSK mice also promotes tumor progression. Single-cell RNA sequencing analyses of subcutaneous tumors from TSK and WT mice revealed tumor-specific changes in the composition and phenotype of various cell populations. The most consistent alteration in TSK mice included a higher neutrophil-to-lymphocyte ratio and an enrichment in profibrotic subpopulations of myofibroblasts and macrophages. Conclusions: Our research unveils the TSK mouse as a valuable model for studying the intricate connections between systemic sclerosis and cancer Full article

Contemporary diabetes management is progressively moving away from a glucocentric approach, with growing expectations that novel antidiabetic agents offer benefits beyond glycaemic control. Sodium–glucose cotransporter 2 inhibitors (SGLT2i) have emerged as a cornerstone in the treatment of type 2 diabetes mellitus (T2DM). In addition to reducing blood glucose levels by promoting renal glucose excretion, these agents contribute significantly to cardio–renal–metabolic protection and are associated with improved cardiovascular outcomes and prolonged survival. Although SGLT2 inhibitors do not exhibit a class effect in all clinical aspects, growing evidence suggests their potential in a variety of additional therapeutic areas. We conducted an in-depth review of current scientific literature and clinical studies regarding this class of drugs. SGLT2 inhibitors demonstrate neuroprotective properties and may provide benefits in neurodegenerative disorders such as Alzheimer’s and Parkinson’s disease, potentially through the improvement of mitochondrial function and attenuation of inflammatory responses. Their anti-inflammatory and antioxidative effects are closely linked to reductions in cardiac and renal fibrosis. Other observed benefits include weight loss, improved insulin sensitivity, normalization of serum uric acid, and a reduction in hepatic steatosis—each with important metabolic implications. Furthermore, SGLT2 inhibitors have been shown to positively influence iron metabolism and improve erythrocyte indices. Emerging data also indicate beneficial effects in women with polycystic ovary syndrome. Another promising area of investigation involves the modulation of Klotho protein expression and support of vascular homeostasis. In oncology, SGLT2 inhibitors are gaining attention, with encouraging preclinical results observed in malignancies such as pancreatic, thyroid, breast, and lung cancers. Based on a comprehensive evaluation of the existing body of evidence, it is anticipated that the clinical indications for SGLT2 inhibitors will expand beyond the cardio–renal–metabolic axis in the near future. Full article

Cancer-associated fibroblasts (CAFs) constitute a heterogeneous population of cells within the tumor microenvironment and are associated with cancer development and drug resistance. The absence of a universal classification for CAFs hinders their research and therapeutic targeting. To define CAF phenotypes, we developed patient-derived cell cultures of breast cancer (BC) and validated and characterized four distinct CAF subtypes (S1–S4) by Costa’s classification. Three out of five primary cell cultures of BC demonstrated different functional features rather than fixed cellular states due to the plasticity of the CAF phenotype. CAF crosstalk with cancer cells supported their survival in the presence of anticancer drugs. Based on the analysis of the cytotoxic effect of doxorubicin, cisplatin and tamoxifen, it was demonstrated that CAF-S4 and CAF-S1 cells were sensitive to the action of all drugs investigated, despite the fact that they possessed different mechanisms of action. CAF-S2 cells exhibited the highest level of resistance to the antitumour agents. Homotypic and heterotypic spheroids with CAFs could be used to model the fibrotic area of BC in vitro. The patient-derived cell cultures of CAFs formed spheroids. Hypoxia-activated CAF-S4 have been shown to stimulate the metastatic potential of triple-negative BC cells in a heterotypic spheroid model. Consequently, this study could be a starting point for the development of novel therapeutic strategies that target CAFs and their interactions with cancer cells. Full article

Introduction: Breast cancer therapy is a common cause of lymphedema. The accumulation of protein-rich fluid in the affected extremity leads to a progressive path—swelling, inflammation, and fibrosis—namely, irreversible changes. Methods: A scientific literature analysis was performed on PubMed/Medline, Scopus, Web of Science (WoS), the Cochrane Central Register of Controlled Trials (CENTRAL), and the Physiotherapy Evidence Database (PEDro) from inception until 30 June 2024. Results: Breast cancer-related lymphedema (BCRL) is indeed an important healthcare burden both due to the significant patient-related outcomes and the overall social impact of this condition. Even though lymphedema is not life-threatening, the literature underlined harmful consequences in terms of pain, infections, distress, and functional impairment with a subsequent and relevant decrease in quality of life. Currently, since there is no cure, the therapeutic approach to BCRL aims to slow disease progression and prevent related complications. A comprehensive overview of postmastectomy lymphedema is offered. First, the pathophysiology and risk factors associated with BCRL were detailed; then, diagnosis modalities were depicted highlighting the importance of early detection. According to non-negligible changes in patients’ everyday lives, novel criteria for patients’ functioning assessment are reported. Regarding the treatment modalities, a wide array of conservative and surgical methods both physiologic and ablative were analyzed with their own outcomes and downsides. Conclusions: Combined strategies and multidisciplinary protocols for BCRL, including specialized management by reconstructive surgeons and physiatrists, along with healthy lifestyle programs and personalized nutritional counseling, should be compulsory to address patients’ demands and optimize the treatment of this harmful and non-curable condition. The Lymphedema-specific ICF Core Sets should be included more often in the overall outcome evaluation with the aim of obtaining a comprehensive appraisal of the treatment strategies that take into account the patient’s subjective score. Full article

Background: Exophiala dermatitidis is a dematiaceous, thermotolerant, yeast-like fungus increasingly recognized as an opportunistic pathogen in chronic airway diseases. While commonly associated with cystic fibrosis, its clinical significance in non-cystic fibrosis bronchiectasis (NCFB) remains unclear. Case Presentation: We report the case of a 66-year-old immunocompetent woman with a history of breast cancer in remission and NCFB, who presented with chronic cough and dyspnea. Chest CT revealed bilateral bronchiectasis with new pseudonodular opacities. Bronchoalveolar lavage cultures identified E. dermatitidis, along with Pseudomonas aeruginosa and methicillin-sensitive Staphylococcus aureus. Given clinical stability and the absence of systemic signs, initial therapy included oral voriconazole, levofloxacin, doxycycline, and inhaled amikacin. Despite persistent fungal isolation on repeat bronchoscopy, the patient remained asymptomatic with stable radiologic and functional findings. Antifungal therapy was discontinued, and the patient continued under close monitoring. The patient exhibited clinical and radiological stability despite repeated fungal isolation, reinforcing the hypothesis of persistent colonization rather than active infection. Discussion: This case underscores the diagnostic challenges in distinguishing fungal colonization from true infection in structurally abnormal lungs. In NCFB, disrupted mucociliary clearance and microbial dysbiosis may facilitate fungal persistence, even in the absence of overt immunosuppression. The detection of E. dermatitidis should prompt a comprehensive evaluation, integrating clinical, radiologic, and microbiologic data to guide management. Voriconazole is currently the antifungal agent of choice, though therapeutic thresholds and duration remain undefined. Conclusions: This report highlights the potential role of E. dermatitidis as an under-recognized respiratory pathogen in NCFB and the importance of a multidisciplinary, individualized approach to diagnosis and treatment. This case underscores the need for further research on fungal colonization in NCFB and the development of evidence-based treatment guidelines. Further studies are needed to clarify the pathogenic significance, optimal management, and long-term outcomes of E. dermatitidis in non-CF chronic lung diseases. Full article

Breast cancer-related lymphedema (BCRL) is the most common cause of secondary lymphedema in the Western world and occurs in up to one-third of breast cancer survivors following axillary lymph node dissection (ALND). Compression of the affected limb is a mainstay of therapy. Surgical management of BCRL involves excision of excess fibroadipose tissue and physiologic procedures to improve fluid retention in the limb. Once lymphedema is established, the inflammatory cascade and fibrosis render the disease hard to reverse. The purpose of this review is to elucidate existing management strategies for prevention of breast cancer-related lymphedema. A literature search was conducted using PubMed, Ovid, Embase, and Scopus. Articles that included management strategies for prevention of BCRL were selected for review. Immediate lymphatic reconstruction (ILR) is a microsurgical technique that connects disrupted axillary lymphatic vessels to nearby veins by lymphovenous anastomoses at the time of ALND and has been shown to reduce rates of lymphedema from 30% to 4–12%. BCRL remains incurable. Immediate lymphatic reconstruction has emerged as a preventative strategy to reduce rates of lymphedema in breast cancer patients. Full article

Background: Mastectomy, a common treatment for breast cancer, often leads to complications such as pain, fibrosis, restricted mobility, lymphedema, reduced strength in the affected arm, and emotional distress. Non-pharmacological therapies, including massage therapy, offer a holistic approach to managing these symptoms. The aim of this study was to analyze the effects of massage therapy on the symptomatology in women post-mastectomy for breast cancer. Methods: A systematic review was conducted following PRISMA guidelines. Databases including PubMed, Cochrane, PEDro, Dialnet, Science Direct, and Scopus were searched for relevant studies published in English or Spanish over the past 16 years. The search was conducted in March 2025. Inclusion criteria encompassed controlled and uncontrolled clinical trials, quasi-experimental studies, retrospective analyses, and secondary trial analyses involving women aged 45–64 who received massage therapy as a complementary treatment. Results: Twenty-six studies involving 1522 participants were included. Interventions assessed were manual lymphatic drainage, myofascial release, foot massage, classical massage, and the Cyriax technique. The key findings demonstrated significant benefits, including improved range of motion, reduced arm circumference and lymphedema volume, enhanced quality of life, and increased relaxation. Conclusions: According to the results of this systematic review, massage therapy interventions can have a positive impact on the symptomatology in women post-mastectomy for breast cancer and may represent a suitable complementary approach to post-mastectomy breast cancer treatment. Full article

During radiotherapy, X-rays can deliver significant doses of ionising radiation to both cancerous and healthy tissue, often leading to undesirable side effects that compromise patient outcomes. While the cellular effects of such therapeutic X-ray exposures are well studied, the impact on extracellular matrix (ECM) proteins remains poorly understood. This study characterises the response of ECM proteins, including the major tissue components collagen I and fibronectin (FN), to X-ray doses similar to those used in clinical practice (50 Gy, as employed in breast radiotherapy, and 100 Gy), using a combination of gel electrophoresis, biochemical assays, and mass spectrometry-based peptide location fingerprinting (PLF) analysis. In purified protein solutions, 50 Gy X-ray exposure led to the fragmentation of constituent collagen I α chains. Irradiation of purified plasma FN (pFN) induced localised changes in peptide yields (detected by liquid chromatography and tandem mass spectrometry (LC-MS/MS) and PLF) and enhanced its binding to collagen I. In complex environments, such as newly synthesised fibroblast-derived ECM and mature ex vivo breast tissue, X-ray exposure induced peptide yield changes in not only collagen I and FN but also key basement membrane proteins, including collagen IV, laminin, and perlecan. Intracellular proteins associated with gene expression (RPS3, MeCP2), the cytoskeleton (moesin, plectin), and the endoplasmic reticulum (calnexin) were also found to be impacted. These X-ray-induced structural changes may impair the ECM integrity and alter cell–ECM interactions, with potential implications for tissue stiffening, fibrosis, and impaired wound healing in irradiated tissues. Full article

Background/Objectives: As the incidence of breast cancer increases, reliable, effective, and innovative solutions are required for breast deformities following breast-conserving surgery. We aimed to evaluate the biocompatibility and efficacy of optimized three-dimensional (3D) micro-nanofiber scaffolds and demonstrate their clinical potential through preclinical experiments. Methods: Seven-week-old male Sprague-Dawley rats were randomized into four groups. Group I (control group) received a 2-dimensional (2D) micro-nanofiber scaffold weighing 0.2 g; Groups II–IV received 3D micro-nanofiber scaffolds weighing 0.2, 0.3, and 0.6 g, respectively. These were subcutaneously implanted into the dorsal region and harvested with the surrounding tissues at 4, 8, and 16 weeks for histological evaluation. Results: The number of inflammatory cells was higher in Group IV than in Groups II and III at 4 weeks, with a significant increase in Group IV (p < 0.01) compared with that in Group I. At 8 weeks, it was significantly increased in Group III compared with that in Group I. Furthermore, at 16 weeks, it was significantly reduced in Group IV (p < 0.05) compared with that in Group I. The fibrosis depth in the 3D scaffolds revealed significant differences in Groups II, III, and IV (p < 0.001) compared with Group I at 4 weeks. The collagen fiber densities in the 3D groups were higher than those in the 2D group at 8 and 16 weeks. There were no statistically significant differences between the 3D groups. Conclusions: Absorbable 3D micro-nanofiber scaffolds enhance tissue integration and extracellular matrix formation following post-mastectomy breast reconstruction. Full article

This article profiles 27 innovative advancements in small-molecule drugs approved by the U.S. Food and Drug Administration (FDA) in 2024. These drugs target various therapeutic areas including non-small cell lung cancer, advanced or metastatic breast cancer, glioma, relapsed or refractory acute leukemia, urinary tract infection, Staphylococcus aureus bloodstream infections, nonalcoholic steatohepatitis, primary biliary cholangitis, Duchenne muscular dystrophy, hypertension, anemia due to chronic kidney disease, extravascular hemolysis, primary axillary hyperhidrosis, chronic obstructive pulmonary disease, severe alopecia areata, WHIM syndrome, Niemann–Pick disease type C, schizophrenia, supraventricular tachycardia, congenital adrenal hyperplasia, and cystic fibrosis. Among these approved small-molecule drugs, those with unique mechanisms of action and designated as breakthrough therapies by the FDA represent a significant proportion, highlighting ongoing innovation. Notably, eight of these drugs (including Rezdiffra^®, Voydeya^®, Iqirvo^®, Voranigo^®, Livdelzi^®, Miplyffa^®, Revuforj^®, and Crenessity^®) are classified as “first-in-class” and have received breakthrough therapy designation. These agents not only exhibit distinct mechanisms of action but also offer substantial improvements in efficacy for patients compared to prior therapeutic options. This article offers a comprehensive analysis of the mechanisms of action, clinical trials, drug design, and synthetic methodologies related to representative drugs, aiming to provide crucial insights for future pharmaceutical development. Full article

Background: The mechanical conditioning (MeCo) score is a multigene expression signature that is acquired by cancer cells in the primary breast tumor and is reflective of their responsiveness to ECM stiffness caused by tumor fibrosis. Chromatin remodeling downstream of mechanotransduction allows cancer cells to retain these acquired aggressive features even in the absence of mechanical stimulation from the primary tumor microenvironment, for instance, after dissemination through systemic circulation during metastasis. Importantly, patients who have high MeCo score tumors are at higher risk of developing metastatic breast cancer, compared to those with low MeCo scores. Moreover, circulating tumor cells (CTCs) are associated with a higher rate of metastatic dissemination, making CTC detection in the circulation of patients with breast cancer a significant prognostic biomarker for breast cancer metastasis. Beyond their enumeration per blood volume units, specific prognostic features of CTCs are not fully explored. We sought to determine whether MeCo scores increase stepwise along the metastatic cascade, from primary tumors to CTCs to distant metastatic colonization, using patient-matched biopsies. Methods: CTCs were isolated from the peripheral blood of two patient cohorts: patients with early-stage breast cancer using immunomagnetic enrichment/FACS methodology; and patients with late-stage breast cancer using the ANGLE Parsortix microfluidics system. Gene expression profiling using RNA-seq was performed on CTCs and matched primary tumors (PTs) in the early-stage cohort, and on CTCs and matched metastases (METs) for the late-stage cohorts. A quantile normalization approach was used to allow comparison across cohorts and MeCo scores were computed for all samples. The Wilcoxon matched-pairs signed rank test was performed for the comparison of MeCo scores from matching samples within each cohort; the Mann–Whitney unpaired test was used to compare MeCo scores of CTCs across cohorts. Results: In 12 pairs of patients with early-stage breast cancer, MeCo scores in CTCs were significantly higher than in their matched PTs (p = 0.026). Additionally, in 26 pairs of metastatic patient CTCs and METs, MeCo scores were significantly higher in METs compared to matched CTCs (p = 0.0004). MeCo scores of CTCs were similar between patients with early- and late-stage breast cancers, despite differing CTC isolation strategies (epitope-dependent and microfluidics size gradient). Notably, 98% of the genes in the MeCo score were present across evaluable CTC, MET, and PT samples. Conclusions: Our results show that the MeCo score is higher in CTCs than in PTs, and higher in METs compared to CTCs, in early- and late-stage breast cancer, respectively (i.e., PT < CTC < MET). Therefore, the MeCo score is progressively higher throughout the metastatic cascade in breast cancer. These findings demonstrate that mechanical conditioning from primary tumors is retained during metastatic progression, after mechanical induction by ECM stiffness is lost, as cancer cells disseminate through systemic circulation. Additionally, these findings support that cancer cells with higher MeCo scores are more competent with—and potentially selected for—metastatic progression. Importantly, these findings provide a novel feature of CTCs, mechanical conditioning (MeCo), which is associated with higher capacity for metastasis. Furthermore, since the CTC MeCo score is elevated even in early-stage breast cancer, it could provide, in addition to CTC enumeration, a potential prognostic indicator to improve metastatic risk assessment in early disease. Full article

Background: The processing of harvested fat for transplantation is critical to fat graft performance. In breast reconstruction, larger volumes of fat are being grafted and, in some clinical cases, are being implanted within radiated tissue. This preclinical animal study evaluated the effects of radiation on retention volume and fat graft quality after processing by decantation or REVOLVE™ technology (Allergan Aesthetics, an AbbVie Company), a filtration-based device that can process lipoaspirates and remove unwanted contaminants prior to grafting. Methods: Lipoaspirate was collected from human donors (n = 6), processed using either REVOLVE™ technology or decantation, and implanted (0.5 cc) into 60 athymic mice for 4 weeks with or without a single 35-Gy radiation dose 12 weeks prior. Volume composition, MRI, and weight-based volumetric assessment of grafted fat were performed and compared between radiated and non-radiated mice. Results: Volume composition analysis demonstrated significantly higher fat content and lower aqueous fluid with REVOLVE™ technology than with decantation, with minimal cellular debris and free oil. MRI-based and weight-based volume analysis demonstrated a significantly higher percent retention with REVOLVE™ technology than decantation in nonirradiated and irradiated sites, respectively. Pathology scoring showed a significant decrease in fibrosis within grafts processed with REVOLVE™ technology in nonirradiated sites. Conclusions: Results suggest that fat processed using REVOLVE™ technology provides better early volume retention and quality of fat grafts compared to decantation, both in healthy and radiation-treated surgical sites. Full article