Cancer and Metastasis Reviews最新文献

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.

Lung cancer is a leading global cause of mortality, with non-small cell lung cancer (NSCLC) accounting for a significant portion of cases. Immune checkpoint inhibitors (ICIs) have transformed NSCLC treatment; however, many patients remain unresponsive. ICI resistance in NSCLC and its association with cellular plasticity, epithelial-mesenchymal transition (EMT), enhanced adaptability, invasiveness, and resistance is largely influenced by epigenetic changes, signaling pathways, tumor microenvironment, and associated immune cells, fibroblasts, and cytokines. Immunosuppressive cells, including M2 tumor-associated macrophages, myeloid-derived suppressor cells, and regulatory T cells, contribute to resistance by suppressing the immune response. This cellular plasticity is influenced when B cells, natural killer cells, and T cells are exhausted or inhibited by components of the tumor microenvironment. Conversely, diverse T cell, NK cell, and B cell subsets hold potential as predictive response markers particularly cytotoxic CD8⁺ T cells, effector memory T cells, activated T cells, tumor infiltrated NK cells, tertiary lymphoid structures, etc. influence treatment response. Identifying specific gene expressions and immunophenotypes within T cells may offer insights into early clinical responses to immunotherapy. ICI resistance in NSCLC is a multifaceted process shaped by tumor plasticity, the complex tumor microenvironment, and dynamic immune cell changes. Comprehensive analysis of these factors may lead to the identification of novel biomarkers and combination therapies to enhance ICI efficacy in NSCLC treatment.

The role of natural killer (NK) cells as immune effectors is well established, as is their utility as immunotherapeutic agents against various cancers. However, NK cells' anti-cancer roles are suppressed in cancer patients by various immunomodulatory mechanisms which alter these cells' identity, function, and potential for immunosurveillance. This manifests in abnormal NK cell responses accompanied by changes in phenotypic or genotypic identity, giving rise to specific NK cell subsets that are either hypofunctional or, more broadly, defective in their responses. Anergy, senescence, and exhaustion are some of the terms that have been used to define and characterize these NK cell functional states. These responses vary not only with cancer type but also NK cell location within tissues. Collectively, these phenomena suggest a highly plastic nature of NK cell biology in tumors. In this review, we present and discuss a summary of these functionally distinct states and provide an overview of how NK cells behave at different locations within the context of cancer.

Nerve signaling within the tumor microenvironment (TME) plays a critical role in the initiation, progression, and metastasis of solid tumors. Due to their highly responsive behavior and activation upon injury and cancer onset, this review specifically focuses on how sympathetic nerves rewire the TME. Within tumors, sympathetic nerves closely interact with various TME components, and their combined signaling often shifts tumor-intrinsic physiology toward tumor-supportive phenotypes. In turn, the TME components, such as myeloid cells, lymphoid cells, extracellular matrix (ECM), endothelial cells, cancer associated fibroblasts (CAFs), and Schwann cells, secrete neurotrophic and axon guidance factors that influence both sympathetic outgrowth and tumor cell behavior, further exacerbating tumor progression and metastasis. Here, we review the current evidence on the multidirectional impacts of sympathetic nerves and both immune and non-immune TME components, the nature of these communication processes, and how exploring these interactions may inform future therapeutics to impair cancer progression and metastasis.

Mutations in the KRAS gene are well-known tumourigenic drivers of colorectal, pancreatic and lung cancers. Mechanistically, these mutations promote uncontrolled cell proliferation and alter the tumour microenvironment during early carcinoma stages. Given their critical carcinogenic functions, significant progress has been made in developing KRAS inhibitors for cancer treatment. However, clinical applications of these KRAS inhibitor compounds are limited to specific cancer types which carry the relevant KRAS mutations. Additionally, clinical findings have shown that these compounds can induce moderate to serious side effects. Therefore, new approaches have emerged focusing on the development of universal therapeutics capable of targeting a wider range of KRAS mutations, minimising toxicity and enhancing the therapeutic efficacy. This review aims to examine these therapeutic strategies in the context of cancer treatment. It firstly provides an overview of fundamental KRAS biology within the cell signalling landscape and how KRAS mutations are associated with cancer pathogenesis. Subsequently, it introduces the development of current KRAS inhibitors which target certain KRAS mutants in different types of cancer. It then explores the potential of gene therapy approaches, including siRNA, miRNA and CRISPR methodologies. Furthermore, it discusses the use of lipid-based nanocarriers to deliver gene cargos for targeting KRAS gene mutants. Finally, it provides the insights into the future prospects for combatting KRAS mutation-associated cancers.

Cancer stem cells play an important role in tumor progression and chemotherapy resistance. Leucine-rich G repeat-containing protein-coupled receptor 5 (LGR5) has been identified as a cancer stem cell marker in several cancer types. LGR5 is involved in cancer development and progression via several pathways including WNT/β-catenin signaling pathway. LGR5 plays a role in tumor progression by promoting cancer cell migration, invasion, metastasis, and angiogenesis in many cancers including colorectal, brain, gastric, and ovarian cancer. This review summarises the current knowledge on the expression and functional role of LGR5 in cancers, the molecular mechanisms regulated by LGR5, and the relationship between LGR5 and chemotherapy resistance. The review also includes highlights potential strategies to inhibit LGR5 expression and function. The majority of functional studies have shown that LGR5 plays an important role in promoting cancer progression, metastasis and chemotherapy resistance however, in some contexts LGR5 can also activate tumor-suppressive pathways and LGR5 negative cells can also promote cancer progression. The review highlights that targeting LGR5 is a promising anti-cancer treatment but the functional effect of LGR5 on tumor cells is complex may be dependent on cancer type, tumor microenvironment and cross-talk with other molecules in the LGR5 signaling pathway.