Medical Oncology最新文献

Oral squamous cell carcinoma (OSCC) is the most prevalent form of head and neck squamous cell carcinoma (HNSCC), characterized by high incidence rates, frequent recurrence and metastasis, and low survival rates. KLHL4, a member of the Kelch-like family proteins, plays a significant role in cancer. However, the role of KLHL4 in OSCC remains largely unexplored. In this study, we first identified the aberrant overexpression of KLHL4 in OSCC tissues through Western blotting and immunohistochemistry. Subsequent experiments, including qPCR, colony formation assays, scratch assays, and transwell invasion and migration assays, demonstrated that knockdown of KLHL4 inhibits OSCC growth, migration and invasion in vitro. Furthermore, through the establishment of subcutaneous xenograft models and lung metastasis models in nude mice, we revealed that KLHL4 knockdown suppresses tumor growth and metastasis in vivo. We also found that KLHL4 knockout inhibited 4NQO-induced OSCC progression. Mechanistically, co-immunoprecipitation confirmed the physical interaction between KLHL4 and EGFR, while rescue experiments using EGF and Afatinib demonstrated the functional dependency of KLHL4 on EGFR pathway activation. Clinical analysis of a 112-case OSCC tissue microarray revealed that high KLHL4 expression correlated significantly with lymph node metastasis and predicted poor patient overall survival, which was independently validated in a public HNSCC cohort. Overall, our research highlights the critical role of KLHL4 in the malignant progression of OSCC through upregulating the EGFR signaling pathway, indicating its potential as a therapeutic target for OSCC treatment.

Adeno-associated virus (AAV) has emerged as a pivotal vector for cancer gene therapy due to its low immunogenicity, non-pathogenicity, and sustained transgene expression capacity. However, the heterogeneity and complexity of the tumor microenvironment (TME) significantly constrain the delivery efficiency and targeting precision of AAV in solid tumors. Dense extracellular matrix, acidic and hypoxic conditions, and immunosuppressive signaling networks collectively impede effective AAV transduction while increasing off-target risks. To overcome these barriers, recent advances have introduced interdisciplinary optimization strategies, including dynamic engineering of AAV capsids, TME-responsive gene expression systems, and biomimetic camouflage technologies to enhance immune evasion and tumor targeting. Furthermore, data-driven AAV engineering, integrating machine learning and high-throughput screening, has significantly accelerated the development of next-generation vectors. This review systematically summarizes intelligent design strategies for TME-responsive AAV vectors and their progress in precision oncology, with a focus on overcoming key delivery barriers to achieve highly efficient and low-toxicity cancer therapy.

Tumor hypoxia poses a major challenge in tumor therapy. Many strategies have been explored to alleviate tumor hypoxic microenvironment to improve the efficacy of tumor therapy. Ultrasound-stimulated microbubbles cavitation (USMC) was proved to improve tumor perfusion, and thus to alleviate tumor hypoxia. The synergistic role of USMC in tumor therapy has been identified by several preclinical and clinical studies. The effect of USMC on improving tumor perfusion is influenced by many factors, and the stability and reproducibility of this effect in long-term tumor treatment remain to be explored. In this study, we established rabbit VX2 tumor model. Fifteen tumor-bearing rabbits were enrolled to compare the effects of USMC with two different mechanical indexes (MIs). The results of contrast-enhanced ultrasound (CEUS) imaging showed that USMC with MI of 0.25 could improve the tumor perfusion better compared with MI 0.40. Then we conducted repeated USMC treatments on tumor-bearing rabbits once a week for six weeks. The results of CEUS showed that USMC with appropriate parameters could always enhance the tumor perfusion although the tumor had developed. Transmission electron microscopy revealed that tumors received multiple USMC treatments had more integral vascular structures compared with the control. Immunofluorescence staining showed that tumors received multiple USMC treatments had higher overlap coefficient of CD31 and intercellular cell adhesion molecule-1, indicating the normalization of tumor vasculature. In conclusion, USMC with appropriate parameters has stability and reproducibility in improving tumor perfusion. And multiple USMC treatments could potentially promote tumor vascular normalization, which is beneficial for tumor therapy.

Pathologically, primary liver cancer is a heterogeneous, aggressive malignancy and encompasses hepatocellular carcinoma, intrahepatic cholangiocarcinoma, and other rare tumors. This cancer remains the fifth most common malignancy in men and the eighth in women and the fourth leading cause of cancer-related mortality worldwide. Clinically, most liver cancer occurs typically from a background of cirrhosis and chronic inflammation. Liver cancer remains difficult to treat; small-molecule kinase inhibitors such as sorafenib and lenvatinib have only limited clinical benefit. Therefore, an urgent need exists to develop novel drugs for the treatment of liver cancer. Triterpenoids, consisting of six isoprene units, are structurally diverse secondary metabolites and possess versatile biological activities including immunomodulatory and antitumor activities. In this review, we discuss the therapeutic potential of natural triterpenoids in liver cancer, primarily focusing on their possible mechanisms involving induction of cell cycle arrest, initiation of apoptosis, activation of autophagy, stimulation of antitumor immune response, suppression of angiogenesis and metastasis, and enhancement of radio/chemo-sensitivity. We also present the current challenges that impede their translation to clinical practices. We conclude that natural triterpenoids could serve as potential candidates for developing liver cancer therapies, based on the current preclinical evidence. However, their clinical translation requires further validation. Hopefully, the knowledge gained from this review will outline future research directions and identify current research priorities in this field.

Lung cancer is one of the leading causes of death worldwide. Cancer metastases are responsible for 90% of cancer-related deaths. In view of the high incidence and mortality of lung cancer, there is still an urgent clinical need to improve the early diagnosis of lung cancer and explore new therapeutic methods and targets to improve the prognosis of patients. By targeting promoter or enhancer regions of related genes, histone methylation modification dynamically regulates gene expression and activation of signaling pathways, and is involved in mediating malignant biological processes such as proliferation, invasion and metastasis of tumor cells. GSK-J4 is a novel small molecule inhibitor of the JMJD3 and UTX family of selective histone demethylases, which shows good anticancer activity against various types of tumors by inhibiting H3K27me3 demethylation. The aim of this study was to investigate the effects of GSK-J4 on proliferation, migration, invasion and epithelial-mesenchymal transformation (EMT) of TGF-β1-induced non-small cell lung cancer (NSCLC) cell lines A549 and H1299. The effect of GSK-J4 on cell proliferation was detected by CCK8, clonal formation assay, immunofluorescence and flow cytometry. The effects of GSK-J4 on the migration and invasion of A549 and H1299 cells induced by TGFβ1 were examined by wound healing assay, Transwell migration assay, and then, the expression changes of related markers were detected by RT-qPCR and western blot. Finally, GSK-J4 was verified to inhibit tumor growth in vivo by constructing a mouse model of tumor implantation in situ, and observed its effectiveness and safety. GSK-J4 inhibited proliferation and promoted apoptosis of A549 and H1299. GSK-J4 inhibited EMT, invasion and migration of TGFβ1-induced NSCLC. GSK-J4 inhibits EMT, invasion and migration of TGFβ1-induced NSCLC through the classical Wnt/β-catenin signaling pathway. In situ tumor model, GSK-J4 administration alone effectively reduced tumor growth in nude mice, with the tumor size being notably less than in the control group. IHC analysis showed that the expression of Ki-67 in GSK-J4 administration group was lower than that in control group. HE staining showed that GSK-J4 had no significant effect on the histopathology of heart, liver, lung, kidney and other major organs of mice. GSK-J4, an inhibitor of histone demethylase, elevated the level of H3K27me3 by suppressing JMJD3/UTX activity, thus curbing NSCLC cell growth and encouraging cell death. Concurrently, GSK-J4 played a role in preventing TGFβ1-triggered EMT, invasion, and migration. Consequently, targeting histone methylation modification and the small molecule inhibitor GSK-J4 is anticipated to be an effective treatment strategy and a novel method for NSCLC.

Exosomes are increasingly recognized as central regulators of organ-specific metastasis, and this review concentrates on their contribution to lung-directed dissemination. Yet, a detailed and integrative synthesis of how exosomes contribute to lung-directed metastatic spread-and what these mechanisms mean for clinical translation-remains largely absent from the current literature. Extracellular vesicles (EVs), particularly exosomes measuring 30-150 nm, are nanoscale, lipid bilayer-enclosed structures secreted by nearly all cell types. In cancer, tumor-derived exosomes act as potent mediators of intercellular signaling, enabling metastatic spread by modulating inflammation, angiogenesis, extracellular matrix dynamics, and immune evasion. Their molecular cargo, especially integrin profiles, plays a decisive role in determining metastatic tropism: integrins α6β4 and α6β1 are strongly associated with pulmonary colonization, while αvβ5 directs metastasis toward the liver. In malignancies such as breast, colorectal, melanoma, and pancreatic cancer, exosomal proteins and RNAs remodel the lung microenvironment, enhancing vascular permeability and attracting stromal and immune components that establish a receptive pre-metastatic niche. Clinically, exosomes are emerging as powerful liquid biopsy biomarkers and as promising platforms for targeted drug delivery. Advances in EV bioengineering now permit tailoring of surface molecules and cargo to improve pulmonary selectivity, for instance, supporting selective delivery of therapeutic payloads to pulmonary tumors or altering immune dynamics within the lung microenvironment, while omics-based and imaging technologies support detailed profiling and tracking. Early clinical trials of exosome-derived vaccines and therapeutic carriers have demonstrated feasibility and safety, although no EV-based therapy has yet achieved regulatory approval. This review integrates mechanistic insights, niche biology, and translational advances to highlight the unique role of exosomes in lung-specific metastasis and their potential as diagnostic and therapeutic tools in precision oncology.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma (NHL). Targeting fatty acid metabolism pathway represents a promising therapeutic strategy, particularly for patients with refractory or relapsed DLBCL. In this study, fatty-acid metabolism index (FMI) signature including 20 genes was constructed by univariate Cox and LASSO-Cox regression analysis using transcriptomic data from Gene Expression Omnibus database to predict overall survival of DLBCL patients. The FMI signature exhibited a negative association with anti-tumor immune response, with FMI-high patients had decreased immune cell infiltration and downregulated immune-associated signaling pathways. Based on the FMI signature, FASN was identified as the most essential gene that negatively regulated the tumor microenvironment of DLBCL. High FASN expression was associated with reduced anti-tumor immune activity, including decreased immune score, lower T-cell inflamed score, and downregulated expression of IFN molecules. Infiltration of immune cells, including CD4⁺T cells, CD8⁺T cells, dendritic cells, and macrophages were also significantly decreased in FASN-high than FASN-low patients. Accordingly, key signal molecules and chemokines for immune cells exhibited negative correlations with FASN expression. Through FASN knockdown in DB cell line, we further validated that FASN significantly suppressed chemokine secretion and promoted DLBCL proliferation in vitro. The FMI signature can effectively distinguish the prognostic stratification of DLBCL patients, further suggesting that FA metabolism imbalance may play an important role in DLBCL heterogeneity and treatment resistance. FASN is a potential negative regulator of immune microenvironment, providing novel insights into the metabolic-immune crosstalk in DLBCL treatment.

Cancer cells show abnormal nucleotide metabolism and prefer the de novo synthesis pathway. As the key enzymes, Carbamoyl-phosphate synthetase 2, Aspartate transcarbamoylase, and Dihydroorotase (CAD) is overactivated in cancer and promotes pyrimidine de novo synthesis, supplying cancer cells with DNA and RNA biosynthesis precursors. Therefore, the development of drugs targeting CAD might inhibit cancer progression and transformation. Icaritin (ICT) is an isoprenoid flavonoid derivative with a wide range of anticancer activities, however, the mechanism of ICT in regulating pyrimidine biosynthesis in cancer remains unclear. MicroRNAs are involved in carcinogenesis by regulating the expression of target genes, and ICT has been shown to regulate the expression of miRNAs leading to suppressing cancer progression. Using both human normal hepatocytes and liver cancer cells, we found that CAD expression was significantly elevated in cancer cells. Interestingly, although ICT treatment reduced CAD protein levels in liver cancer cells, it increased CAD transcriptional activity. Dual-luciferase reporter assays confirmed miR-18b-5p as a direct regulator of CAD. By transfecting miR-18b-5p mimics or inhibitors, we showed ICT upregulates miR-18b-5p to suppress CAD, inhibiting liver cancer cell proliferation, migration, and colony formation. Furthermore, in a human liver cancer xenograft mouse model, ICT treatment markedly reduced tumor growth and decreased Ki-67 expression, consistent with the in vitro results, CAD protein expression was downregulated, while its mRNA level was upregulated, further supporting a post-transcriptional regulatory mechanism. Overall, ICT plays an anti-liver cancer role by increasing miR-18b-5p at the post-transcriptional level to inhibit CAD expression, which may interfere with the de novo synthesis of pyrimidine and development of liver cancer.

AKR1Cs, as a reductase enzyme family, play a pro-carcinogenic role in various types of cancers, including hormone-related malignancies and non-hormonal tumors. However, there exists a notable scarcity of literature concerning AKR1Cs expression in pancreatic cancer and the subsequent impacts on its progression. Analyzing pancreatic cancer database information by employing advanced bioinformatics techniques to unravel AKR1Cs' intricate involvement in cancer malignancy, their correlation with clinical pathology, prognostic implications, as well as their responsiveness to conventional and immune-based therapies. Furthermore, the role of AKR1C1 in promoting the malignant progression of pancreatic cancer cell lines was validated using cell proliferation assays (EdU labeling and colony formation), and cell migration and invasion experiments including scratch wound healing and Transwell migration/invasion assays. AKR1Cs are not only significantly overexpressed in pancreatic cancer, but also closely associated with poor clinical grading, clinical chemoresistance and poor immune response in pancreatic cancer.Moreover, regulating the expression of AKR1C1 in pancreatic cancer cells will affect its proliferation, migration, invasion and the occurrence of epithelial-mesenchymal transformation (EMT). Our findings are expected to establish AKR1Cs, especially AKR1C1 as a promising therapeutic target for the clinical treatment of pancreatic cancer.

This review provides a summary of recent evidence on vitamin D and osteosarcoma, aiming to elucidate the molecular mechanisms of vitamin D in osteosarcoma and explore its potential role in patient management. Osteosarcoma, a malignant bone neoplasm, is characterized by its aggressive nature, poor prognosis, and metastatic potential, often spreading to the lungs. Its clinical severity highlights the need for early detection, prompt intervention, and comprehensive treatment strategies to improve outcomes and quality of life for individuals affected by it. Circulating 25-hydroxyvitamin D [25(OH)D] is quantified as a measure of vitamin D status. Vitamin D status is utilized as a clinical biomarker to identify vitamin D deficiency. The role of vitamin D in bone health and development is well known, specifically its regulation of calcium-phosphate homeostasis. Furthermore, recent findings identified vitamin D's role in carcinogenesis by regulating cancer cell differentiation, proliferation, apoptosis, and metastatic potential. The involvement of vitamin D-binding protein (VDBP) and its polymorphisms in regulating vitamin D bioavailability has also been recognized. However, these findings are primarily in major cancers such as breast cancer, lung cancer, and colorectal cancer. Evidence pertaining to the fundamental role of bone cancer, in particular osteosarcoma, and vitamin D remains scarce. Nevertheless, the limited evidence showed that maintaining circulating 25(OH)D in osteosarcoma patients is associated with a higher survival rate. Meanwhile, vitamin D supplementation as an adjuvant could potentially increase survival rates and quality of life.