Latest ArticlesMelanoma, the most aggressive form of skin cancer, remains a significant clinical challenge due to the high metastatic potential and drug resistance. This review explores the pivotal roles of angiogenesis and vasculogenic mimicry in melanoma progression and treatment resistance. Angiogenesis, driven primarily by VEGF/VEGFR signaling, is critical for tumor sustenance but is often insufficient under hypoxic conditions, prompting melanoma cells to adapt by forming vascular-like structures (i.e., vasculogenic mimicry). These structures enable melanoma cells to mimic endothelial functions and are linked to increased metastasis and poor prognosis. Molecular drivers, including VE-cadherin, EphA2, and hypoxia-inducible factors, have been identified as key regulators of these processes. Current anti-angiogenic agents have limited efficacy in advanced/metastatic melanoma due to tumor plasticity and the interplay between angiogenesis and vasculogenic mimicry. The review highlights the need for therapeutic strategies targeting both mechanisms, emphasizing the importance of combination treatments to overcome resistance. Future research should aim to elucidate the molecular underpinnings of angiogenesis and vasculogenic mimicry to improve melanoma management and patient outcomes.
Osimertinib (OSI) therapy, a cornerstone in treating non-small cell lung cancer (NSCLC), has been severely limited by rapidly developing acquired resistance. Inhibition of bypass activation using a combination strategy holds promise in overcoming this resistance. Biguanides, with excellent anti-tumor effects, have recently attracted much attention for this potential. The current study investigated whether novel biguanide compounds developed by our team could overcome OSI resistance and the underlying mechanisms were explored.
A comprehensive screening assay using OSI-resistant cells identified the optimal combination of biguanide compounds with OSI. Proteomics, co-immunoprecipitation mass spectrometry, RNA sequencing, and homologous recombination assays were used to elucidate the molecular mechanisms underlying combination therapy. NSCLC tumor tissues, especially OSI-resistant tissues, obtained from our clinic were used to assess the correlations between key proteins and OSI resistance.
SMK-010, a highly potent biguanide compound, effectively overcame OSI resistance in vitro and in vivo. Mechanistical studies showed that BMI1/FGFR1 pathway activation is responsible for OSI resistance. Specifically, silencing BMI1 promoted NEDD4-mediated FGFR1 ubiquitination and proteasomal degradation, whereas SMK-010 treatment induced FGFR1 lysosomal degradation. This reduction in FGFR1 levels impaired homologous recombination, increased DNA damage, and surmounted OSI resistance. Analysis of clinical samples revealed overexpression of BMI1 and FGFR1 in NSCLC tissues and represented potential biomarkers for OSI resistance.
These findings highlight the crucial role of the BMI1/FGFR1 axis in OSI resistance and provide a rational basis for the future clinical application of the biguanide, SMK-010, in combination with OSI.
Neutrophil extracellular traps (NETs) are web-like structures of DNA and proteins that are released by activated neutrophils. While originally identified as antimicrobial defense mechanisms, NETs are now recognized as key modulators of tumor progression. NETs interact with the tumor microenvironment and metabolic pathways in renal cell carcinoma (RCC), which promotes immune evasion and metastasis. This review explores the interplay between NET formation and metabolic reprogramming in RCC, highlighting the implications for immunotherapy resistance and therapeutic targeting. NET-associated signaling, immunometabolism disruption, and current strategies to inhibit NETs in preclinical and clinical settings are discussed. Targeting NETs may represent a promising adjunct in RCC therapy, particularly when integrated with immune checkpoint blockade.
Current clinical staging of pancreatic ductal adenocarcinoma (PDAC) relies predominantly on anatomical resectability, thus limiting its prognostic utility. We developed and validated a pretreatment prognostic grading system incorporating multidimensional parameters.
Patients with histologically confirmed PDAC undergoing curative-intent pancreatectomy were retrospectively enrolled. Independent prognostic determinants of overall survival (OS) and disease-free survival (DFS), identified through multivariable Cox proportional hazards regression, provided the basis for deriving the Tianjin Prognostic Score and its corresponding risk stratification scheme.
Resectability status, lymph node metastasis indicated by imaging, pretreatment serum CA19-9 levels, and the prognostic nutritional score (PNS) independently predicted both OS and DFS. These parameters were integrated into the Tianjin Prognostic Score for PDAC prognosis stratification. The Tianjin-Grade system, subsequently established according to this score, segregated patients into 4 discrete prognostic cohorts with significantly divergent survival outcomes. This system exhibited significantly greater discriminatory ability for prognosis than conventional serum CA19-9 and resectability criteria. Notably, patients classified as having high risk or extremely high risk derived substantial survival benefits from neoadjuvant chemotherapy (NAC), whereas those with low or intermediate risk demonstrated comparable survival outcomes regardless of NAC administration.
The Tianjin-Grade system provides accurate pretreatment prognosis prediction in patients with PDAC through integration of anatomical and biological parameters, thus serving as a reliable tool for prognostic assessment. This system facilitates the development of personalized preoperative therapeutic strategies.
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