Current Cancer Drug Targets - Volume 24, Issue 6, 2024

Glioblastoma (GBM) stands as the most aggressive and lethal among the main types of primary brain tumors. It exhibits malignant growth, infiltrating the brain tissue, and displaying resistance toward treatment. GBM is a complex disease characterized by high degrees of heterogeneity. During tumour growth, microglia and astrocytes, among other cells, infiltrate the tumour microenvironment and contribute extensively to gliomagenesis. Tumour-associated macrophages (TAMs), either of peripheral origin or representing brain-intrinsic microglia, are the most numerous nonneoplastic populations in the tumour microenvironment in GBM. The complex heterogeneous nature of GBM cells is facilitated by the local inflammatory tumour microenvironment, which mostly induces tumour aggressiveness and drug resistance. The immunosuppressive tumour microenvironment of GBM provides multiple pathways for tumour immune evasion, contributing to tumour progression. Additionally, TAMs and astrocytes can contribute to tumour progression through the release of cytokines and activation of signalling pathways. In this review, we summarize the role of the microenvironment in GBM progression, focusing on neuroinflammation. These recent advancements in research of the microenvironment hold the potential to offer a promising approach to the treatment of GBM in the coming times.

Colorectal cancer is one of the most common cancer types worldwide. Since colorectal cancer takes time to develop, its incidence and mortality can be treated effectively if it is detected in its early stages. As a result, non-invasive or invasive biomarkers play an essential role in the early diagnosis of colorectal cancer. Many experimental studies have been carried out to assess genetic, epigenetic, or protein markers in feces, serum, and tissue. It may be possible to find biomarkers that will help with the diagnosis of colorectal cancer by identifying the genes, RNAs, and/or proteins indicative of cancer growth. Recent advancements in the molecular subtypes of colorectal cancer, DNA methylation, microRNAs, long noncoding RNAs, exosomes, and their involvement in colorectal cancer have led to the discovery of novel biomarkers. In small-scale investigations, most biomarkers appear promising. However, large-scale clinical trials are required to validate their effectiveness before routine clinical implementation. Hence, this review focuses on small-scale investigations and results of big data analysis that may provide an overview of the biomarkers for the diagnosis, therapy, and prognosis of colorectal cancer.

Gastrointestinal (GI) cancer is a major health concern due to its prevalence, impact on well-being, high mortality rate, economic burden, and potential for prevention and early detection. GI cancer research has made remarkable strides in understanding biology, risk factors, and treatment options. An emerging area of research is the gut microbiome's role in GI cancer development and treatment response. The gut microbiome, vital for digestion, metabolism, and immune function, is increasingly linked to GI cancers. Dysbiosis and alterations in gut microbe composition may contribute to cancer development. Scientists study how specific bacteria or microbial metabolites influence cancer progression and treatment response. Modulating the gut microbiota shows promise in enhancing treatment efficacy and preventing GI cancers. Gut microbiota dysbiosis can impact GI cancer through inflammation, metabolite production, genotoxicity, and immune modulation. Microbes produce metabolites like short-chain fatty acids, bile acids, and secondary metabolites. These affect host cells, influencing processes like cell proliferation, apoptosis, DNA damage, and immune regulation, all implicated in cancer development. This review explores the latest research on gut microbiota metabolites and their molecular mechanisms in GI cancers. The hope is that this attempt will help in conducting other relevant research to unravel the precise mechanism involved, identify microbial signatures associated with GI cancer, and develop targets.

Background and Objectives: Preliminary experiments have revealed the abnormally high expression level of adropin in pancreatic ductal adenocarcinoma (PDA). This study investigated the role of adropin in the progression of PDA. Methods: The paraffin-embedded samples of 20 patients with PDA were obtained from the hospital biobank, and immunohistochemistry was used to evaluate adropin expression. PDA cell lines were cultured and treated with recombinant adropin or adropin knockdown. Cell behavior was assessed, and the expression of phospho-vascular endothelial growth factor receptor (p-VEGFR2) and other related proteins was detected. The cell-derived xenograft (CDX) of PDA was established, and the effects of adropin or adropin knockdown on tumor growth were observed. Results: The PDA cancer tissues exhibited elevated adropin protein expression compared with the paracancerous tissues, and the expression was positively correlated with carbohydrate antigen 19-9 levels in patients. Adropin significantly promoted the proliferation and migration of PDA cells and upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and matrix metalloprotein 2 (MMP2). After the knockdown of adropin expression or blockade of VEGFR2, the above effects of adropin were significantly reversed. Adropin supplementation significantly accelerated tumor growth in PDA CDX; upregulated the expression of p-VEGFR2, Ki67, cyclin D1, and MMP2; and promoted angiogenesis in tumor tissue microenvironment. However, CDX inoculated with adropin knockdown cells produced the opposite results. Conclusion: Adropin overexpression in PDA promotes cancer cell proliferation and angiogenesis in tumor microenvironment by continuously activating VEGFR2 signaling, thereby creating conditions for tumor progression. Thus, targeting adropin may be an effective anti-PDA strategy.

Background: Immune-checkpoint inhibitors (ICIs) against programmed death (PD)-1/PD-L1 pathway immunotherapy have been demonstrated to be effective in only a subset of patients with cancer, while the rest may exhibit low response or may develop drug resistance after initially responding. Previous studies have indicated that extensive collagen-rich stroma secreted by cancer-associated fibroblasts (CAFs) within the tumor microenvironment is one of the key obstructions of the immunotherapy for some tumors by decreasing the infiltrating cytotoxic T cells. However, there is still a lack of effective therapeutic strategies to control the extracellular matrix by targeting CAFs. Methods: The enhanced uptake of IR-780 by CAFs was assessed by using in vivo or ex vivo nearinfrared fluorescence imaging, confocal NIR fluorescent imaging, and CAFs isolation testing. The fibrotic phenotype down-regulation effects and in vitro CAFs killing effect of IR-780 were tested by qPCR, western blot, and flow cytometry. The in vivo therapeutic enhancement of anti-PD-L1 by IR-780 was evaluated on EMT6 and MC38 subcutaneous xenograft mice models. Results: IR-780 has been demonstrated to be preferentially taken up by CAFs and accumulate in the mitochondria. Further results identified low-dose IR-780 to downregulate the fibrotic phenotype, while high-dose IR-780 could directly kill both CAFs and EMT6 cells in vitro. Moreover, IR-780 significantly inhibited extracellular matrix (ECM) protein deposition in the peri-tumoral stroma on subcutaneous EMT6 and MC38 xenografts, which increased the proportion of tumor-infiltrating lymphocytes (TILs) in the deep tumor and further promoted anti-PD-L1 therapeutic efficacy. Conclusion: This work provides a unique strategy for the inhibition of ECM protein deposition in the tumor microenvironment by targeted regulating of CAFs, which destroys the T cell barrier and further promotes tumor response to PD-L1 monoclonal antibody. IR-780 has been proposed as a potential therapeutic small-molecule adjuvant to promote the effect of immunotherapy.

Background: Lung adenocarcinoma (LUAD) is a major health challenge worldwide with an undesirable prognosis. LINC00982 has been implicated as a tumor suppressor in diverse human cancers; however, its role in LUAD has not been fully characterized. Methods: Expression level and prognostic value of LINC00982 were investigated in pan-cancer and lung cancer from The Cancer Genome Atlas (TCGA) project. Differential expression analysis based on the LINC00982 expression level was performed in LUAD followed by gene set enrichment analysis (GSEA) and functional enrichment analyses. The association between LINC00982 expression and tumor immune microenvironment characteristics was evaluated. A potential ceRNA regulatory axis was identified and experimentally validated. Results: We found that LINC00982 expression was downregulated and correlated with poor prognosis in LUAD. Enrichment analyses revealed that LINC00982 could inhibit DNA damage repair and cell proliferation, but enhance tumor metabolic reprogramming. We identified a competing endogenous RNA network involving LINC00982, miR-183-5p, and ATP-binding cassette subfamily A member 8 (ABCA8). Luciferase assays confirmed that miR-183-5p can interact with LINC00982 and ABCA8. Forced miR-183-5p expression reduced LINC00982 transcript levels and suppressed ABCA8 expression. Conclusions: Our findings revealed the LINC00982/miR-183-5p/ABCA8 axis as a potential therapeutic target in LUAD.

Background: Oral cancer is a malignant tumor with a high impact and poor prognosis. Naringenin, a flavonoid found in citrus fruits and its anti-inflammatory and antioxidant properties offer potential therapeutic benefits. However, limited studies have been conducted on the impact of naringenin on human tongue carcinoma CAL-27 cells. This study aims to elucidate the correlation between naringenin and tongue cancer, thereby identifying a potential therapeutic candidate for drug intervention against tongue cancer. Methods: The effect of naringenin on the apoptosis of CAL-27 cells and its mechanism were studied by cell counting kit-8, mitochondrial membrane potential assay with JC-1, Annexin V-- FITC apoptosis detection, cell cycle, and apoptosis analysis, Reactive Oxygen Species assay and Western blot. Results: The results showed that naringenin significantly induced apoptosis in CAL-27 cells in a dose-dependent manner. Mechanistically, naringenin-induced apoptosis was mediated through the upregulation of Bid and downregulation of Bcl-xl, which led to increased generation of ROS. Conclusion: The findings suggested that naringenin may represent a promising candidate for the treatment of oral cancer by inducing apoptotic cell death via modulation of the Bid and Bcl-xl signaling pathways.