Exosomes deliver lncRNA DARS-AS1 siRNA to inhibit chronic unpredictable mild stress-induced TNBC metastasis

The IL-6/JAK/STAT3 pathway is aberrantly hyperactivated in many types of cancer, and such hyperactivation is generally associated with a poor clinical prognosis. In the tumour microenvironment, IL-6/JAK/STAT3 signalling acts to drive the proliferation, survival, invasiveness, and metastasis of tumour cells, while strongly suppressing the antitumour immune response. Thus, treatments that target the IL-6/JAK/STAT3 pathway in patients with cancer are poised to provide therapeutic benefit by directly inhibiting tumour cell growth and by stimulating antitumour immunity. Agents targeting IL-6, the IL-6 receptor, or JAKs have already received FDA approval for the treatment of inflammatory conditions or myeloproliferative neoplasms and for the management of certain adverse effects of chimeric antigen receptor T cells, and are being further evaluated in patients with haematopoietic malignancies and in those with solid tumours. Novel inhibitors of the IL-6/JAK/STAT3 pathway, including STAT3-selective inhibitors, are currently in development. Herein, we review the role of IL-6/JAK/STAT3 signalling in the tumour microenvironment and the status of preclinical and clinical investigations of agents targeting this pathway. We also discuss the potential of combining IL-6/JAK/STAT3 inhibitors with currently approved therapeutic agents directed against immune-checkpoint inhibitors.

Cancer represents a pathological manifestation of uncontrolled cell division; therefore, it has long been anticipated that our understanding of the basic principles of cell cycle control would result in effective cancer therapies. In particular, cyclin-dependent kinases (CDKs) that promote transition through the cell cycle were expected to be key therapeutic targets because many tumorigenic events ultimately drive proliferation by impinging on CDK4 or CDK6 complexes in the G1 phase of the cell cycle. Moreover, perturbations in chromosomal stability and aspects of S phase and G2/M control mediated by CDK2 and CDK1 are pivotal tumorigenic events. Translating this knowledge into successful clinical development of CDK inhibitors has historically been challenging, and numerous CDK inhibitors have demonstrated disappointing results in clinical trials. Here, we review the biology of CDKs, the rationale for therapeutically targeting discrete kinase complexes and historical clinical results of CDK inhibitors. We also discuss how CDK inhibitors with high selectivity (particularly for both CDK4 and CDK6), in combination with patient stratification, have resulted in more substantial clinical activity.

Breast cancer is one of the most common malignancies among women throughout the world and is the major cause of most cancer-related deaths. Several explanations account for the high rate of mortality of breast cancer, and metastasis to vital organs is identified as the principal cause. Over the past few years, intensive efforts have demonstrated that breast cancer exhibits metastatic heterogeneity with distinct metastatic precedence to various organs, giving rise to differences in prognoses and responses to therapy in breast cancer patients. Bone, lung, liver, and brain are generally accepted as the primary target sites of breast cancer metastasis. However, the underlying molecular mechanism of metastatic heterogeneity of breast cancer remains to be further elucidated. Recently, the advent of novel genomic and pathologic approaches as well as technological breakthroughs in imaging analysis and animal modelling have yielded an unprecedented change in our understanding of the heterogeneity of breast cancer metastasis and provided novel insight for establishing more effective therapeutics. This review summarizes recent molecular mechanisms and emerging concepts on the metastatic heterogeneity of breast cancer and discusses the potential of identifying specific molecules against tumor cells or tumor microenvironments to thwart the development of metastatic disease and improve the prognosis of breast cancer patients.