Cancer and Metastasis Reviews最新文献

Genetic and epigenetic modifications of DNA are involved in cancer initiation and progression. Epigenetic modifications change chromatin structure and DNA accessibility and thus affect DNA replication, DNA repair and transcription. Epigenetic modifications are reversible and include DNA methylation, histone acetylation and histone methylation. DNA methylation is catalysed by DNA methyltransferases, histone acetylation and deacetylation are catalysed by histone acetylases and deacetylases, while histone methylation is catalysed by histone methyltransferases. Epigenetic modifications are dysregulated in several cancers, making them cancer therapeutic targets. Epigenetic drugs (epi-drugs) which are inhibitors of epigenetic modifications and include DNA methyltransferase inhibitors (DNMTi), histone deacetylase inhibitors (HDACi), histone methyltransferase inhibitors (HMTi) and bromodomain and extra-terminal motif protein inhibitors (BETi), have demonstrated clinical success as anti-cancer agents. Furthermore, the combination of epi-drugs with standard chemotherapeutic agents has demonstrated promising anti-cancer effects in pre-clinical and clinical settings. In this review, we discuss the role of epi-drugs in cancer therapy and explore their current and future use in combination with other anti-cancer agents used in the clinic. We further highlight the side effects and limitations of epi-drugs. We additionally discuss novel delivery methods and novel tumour epigenetic biomarkers for the screening, diagnosis and development of personalised cancer treatments, in order to reduce off-target toxicity and improve the specificity and anti-tumour efficacy of epi-drugs.

Ferroptosis, an iron-dependent form of cell death, has been the focus of extensive research over the past decade, leading to the elucidation of key molecules and mechanisms involved in this process. While several studies have highlighted iron sources for the Fenton reaction, the predominant mechanism for iron release in ferroptosis has been identified as ferritinophagy, which occurs in response to iron starvation. However, much of the existing literature has concentrated on lipid peroxidation rather than on the mechanisms of iron release. This review proposes three distinct mechanisms of iron mobilization: ferritinophagy, reductive pathways with selective gating of ferritin pores, and quinone-mediated iron mobilization. Notably, the latter two mechanisms operate independently of iron starvation and rely primarily on reductants such as NADH and O₂•^-. The inhibition of the respiratory chain, particularly under the activation of α-ketoglutarate dehydrogenase, leads to the accumulation of these reductants, which in turn promotes iron release from ferritin and indirectly inhibits AMP-activated protein kinase through excessive iron levels. In this work, we delineate the intricate relationship between iron mobilization and bioenergetic processes under conditions of oxidative stress. Furthermore, this review aims to enhance the understanding of the connections between ferroptosis and these mechanisms.

The efficacy and off-target effects of immune checkpoint inhibitors (ICI) in cancer treatment vary among patients. Monocytes likely contribute to this heterogeneous response due to their crucial role in immune homeostasis. We conducted a systematic review and meta-analysis to evaluate the impact of monocytes on ICI efficacy and immune-related adverse events (irAEs) in patients with cancer. We systematically searched PubMed, Web of Science, and Embase for clinical studies from January 2000 to December 2023. Articles were included if they mentioned cancer, ICI, monocytes, or any monocyte-related terminology. Animal studies and studies where ICIs were combined with other biologics were excluded, except for studies where two ICIs were used. This systematic review was registered with PROSPERO (CRD42023396297) prior to data extraction and analysis. Monocyte-related markers, such as absolute monocyte count (AMC), monocyte/lymphocyte ratio (MLR), specific monocyte subpopulations, and m-MDSCs were assessed in relation to ICI efficacy and safety. Bayesian meta-analysis was conducted for AMC and MLR. The risk of bias assessment was done using the Cochrane-ROBINS-I tool. Out of 5787 studies identified in our search, 155 eligible studies report peripheral blood monocyte-related markers as predictors of response to ICI, and 32 of these studies describe irAEs. Overall, based on 63 studies, a high MLR was a prognostic biomarker for short progression-free survival (PFS) and overall survival (OS) hazard ratio (HR): 1.5 (95% CI: 1.21-1.88) and 1.52 (95% CI:1.13-2.08), respectively. The increased percentage of classical monocytes was an unfavorable predictor of survival, while low baseline rates of monocytic myeloid-derived suppressor cells (m-MDSCs) were favorable. Elevated intermediate monocyte frequencies were associated but not significantly correlated with the development of irAEs. Baseline monocyte phenotyping may serve as a composite biomarker of response to ICI; however, more data is needed regarding irAEs. Monocyte-related variables may aid in risk assessment and treatment decision strategies for patients receiving ICI in terms of both efficacy and safety.

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer worldwide. Its primary risk factors are chronic liver diseases such as metabolic fatty liver disease, non-alcoholic steatohepatitis, and hepatitis B and C viral infections. These conditions contribute to a specific microenvironment in liver tumors which affects mitochondrial function. Mitochondria are energy producers in cells and are responsible for maintaining normal functions by controlling mitochondrial redox homeostasis, metabolism, bioenergetics, and cell death pathways. HCC involves abnormal mitochondrial functions, such as accumulation of reactive oxygen species, oxidative stress, hypoxia, impairment of the mitochondrial unfolded protein response, irregularities in mitochondrial dynamic fusion/fission mechanisms, and mitophagy. Cell death mechanisms, such as necroptosis, pyroptosis, ferroptosis, and cuproptosis, contribute to hepatocarcinogenesis and play a significant role in chemoresistance. The relationship between mitochondrial dynamics and HCC is thus noteworthy. In this review, we summarize the recent advances in mitochondrial alterations and signatures in HCC and attempt to elucidate its molecular biology. Here, we provide an overview of the mitochondrial processes involved in hepatocarcinogenesis and offer new insights into the molecular pathology of the disease. This may help guide future research focused on improving patient outcomes using innovative therapies.

The multidomain protein cargo adaptor p62, also known as sequestosome 1, serves as a shuttling factor and adaptor for the degradation of substrates via the proteasome and autophagy pathways. Regarding its structure, p62 is composed of several functional domains, including the N-terminal Phox1 and Bem1p domains, a ZZ-type zinc finger domain, a LIM protein-binding domain that contains the tumor necrosis factor receptor-associated factor 6 (TRAF6) binding region, two nuclear localization signals (NLS 1/2), a nuclear export signal (NES), the LC3-interacting region (LIR), a Kelch-like ECH-associated protein 1 (KEAP1)-interacting region, and a ubiquitin-associated (UBA) domain. Recent studies have highlighted the critical role of p62 in the development and progression of various malignancies. Overexpression and/or impaired degradation of p62 are linked to the initiation and progression of numerous cancers. While p62 is primarily localized in the cytosol and often considered a cytoplasmic protein, most of the existing literature focuses on its cytoplasmic functions, leaving its nuclear roles less explored. However, an increasing body of research has uncovered p62's involvement in the cellular response to DNA damage. In this review, we summarize the current understanding of p62's molecular functions in malignancies, with particular emphasis on its role in DNA damage repair, highlighting the latest advances in this field.

Breast cancer, with its diverse subtypes like ER-positive, HER-2-positive, and triple-negative, presents complex challenges demanding personalized treatment approaches. The intricate interplay of genetic, environmental, and lifestyle factors underscores its status as a primary contributor to cancer-related fatalities in women globally. Understanding the molecular drivers specific to each subtype is crucial for developing effective therapies. In this landscape, connective tissue growth factor (CTGF), also referred to as cellular communication network factor 2 (CCN2), emerges as a significant player. CTGF regulates critical biological activities like cell growth, invasion, and migration, impacting breast cancer development and progression. It modulates breast tumor microenvironment by promoting angiogenesis, activating cancer-associated fibroblasts (CAFs), and inducing inflammation. The activity of CTGF depends on several factors including oxygen levels, hormone signals, and growth factors and differs according to the type of breast cancer. CTGF can regulate breast cancer cells by activating various signaling pathways and modulating the transcription of other genes that are involved in tumor development and metastasis including S100A4, glucose transporter 3 (GLUT3), and vascular endothelial growth factor (VEGF). The matricellular protein can be considered a potential therapeutic target, as it can promote tumor growth and confer drug resistance in breast cancer. Numerous tactics, including neutralizing antibodies, antisense oligonucleotides, natural compounds, recombinant proteins, and short hairpin RNAs have been suggested to block its function. This review highlights the structure of CTGF, regulation of its expression, and current knowledge of its oncogenic role in breast cancer, as well as focusing on potential therapeutic strategies for targeting CTGF in breast cancer.

Cellular plasticity and the ability to avoid terminal differentiation are hallmarks of cancer. Here, we review the evidence that tumor cells themselves can take on properties of neurons of the central nervous system, which can regulate tumor growth and metastasis. We discuss recent evidence that axon guidance molecules and regulators of electrical activity and synaptic transmission, such as ion channels and neurotransmitters, can drive the oncogenic and invasive properties of tumor cells from a range of cancers. We also review how FDA-approved treatments for neurological disorders are being tested in pre-clinical models and clinical trials for repurposing as anti-cancer agents, offering the potential for new therapies for cancer patients that can be accessed more quickly.

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in patients with non-small cell lung cancer (NSCLC) lacking targetable oncogenic alterations. However, their efficacy in individuals with such genomic alterations remains heterogeneous and poorly understood. In detail, certain oncogenic alterations in TP53, EGFR (uncommon mutations), KRAS (G12C), BRAF (non-V600E), MET (amplifications), FGFR1 and FGFR4, actively modify MAPK, PI3K, and STING signaling, thus remodeling tumoral immune phenotype and are associated with high TMB counts, enriched T lymphocyte tumor infiltration, and high expression of antigen-presenting molecules, supporting their consideration as part of the eligibility criteria for ICIs treatment. Nonetheless, other oncogenic alterations are associated with an immunosuppressive TME, low TMB counts, and downregulation of targetable immune checkpoints, in which novel therapeutic approaches are currently being tested to overcome their intrinsic resistance. In this context, this review discusses the fundamental mechanisms by which frequent driver alterations affect ICIs efficacy in patients with NSCLC, and outlines their prognostic relevance in the era of immunotherapy.

CT chest scans are commonly performed worldwide, either in routine clinical practice for a wide range of indications or as part of lung cancer screening programs. Many of these scans detect lung nodules, which are small, rounded opacities measuring 8-30 mm. While the concern about nodules is that they may represent early lung cancer, in screening programs, only 1% of such nodules turn out to be cancer. This leads to a series of complex decisions and, at times, unnecessary biopsies for nodules that are ultimately determined to be benign. Additionally, patients may be anxious about the status of detected lung nodules. The high rate of false positive lung nodule detections has driven advancements in biomarker-based research aimed at triaging lung nodules (benign versus malignant) to identify truly malignant nodules better. Biomarkers found in biofluids and breath hold promise owing to their minimally invasive sampling methods, ease of use, and cost-effectiveness. Although several biomarkers have demonstrated clinical utility, their sensitivity and specificity are still relatively low. Combining multiple biomarkers could enhance the characterisation of small pulmonary nodules by addressing the limitations of individual biomarkers. This approach may help reduce unnecessary invasive procedures and accelerate diagnosis in the future. This review offers a thorough overview of emerging minimally invasive biomarkers for triaging lung nodules, emphasising key challenges and proposing potential solutions for biomarker-based nodule differentiation. It focuses on diagnosis rather than screening, analysing research published primarily in the past five years with some exceptions. The incorporation of biomarkers into clinical practice will facilitate the early detection of malignant nodules, leading to timely interventions and improved outcomes. Further efforts are needed to increase the cost-effectiveness and practicality of many of these applications in clinical settings. However, the range of technologies is advancing rapidly, and they may soon be implemented in clinics in the near future.

The management of bone metastases (BoM) requires a multidisciplinary approach to prevent complications, necessitating updated knowledge in light of the rapid advancements in systemic treatments and surgical, interventional radiology or radiation techniques. This review aims to discuss efficacy of new systemic treatments on BoM, the benefits of radiotherapy adjunction, and the optimal methods for combining them. Preliminary evidence suggesting reduced efficacy of immune checkpoint inhibitors (ICI), and several multi-kinase inhibitors regarding BoM may encourage early use of radiotherapy (RT). Systemic treatment efficacy modulation by RT and ablative RT strategies are explored. Concerns for increased side effects for several kinase inhibitors and double ICI in combination with RT imply suspending those systemic treatments during RT. Various timing strategies to combine prostate hormone therapies and RT are developed. Emerging internal vectorized radiotherapy molecules necessitate developing new combination strategies with RT. Further prospective data collection and comparative trials should be encouraged.