Abstract
Signal transducer and activator of transcription 3 (STAT3) is a critical transcription factor that has been firmly associated with colorectal cancer (CRC) initiation and development. STAT3 mediates key inflammatory mechanisms in colitis-associated cancer, becomes excessively activated in CRC, and enhances cancer cell proliferation, tumor growth, angiogenesis, invasion, and migration. STAT3 hyperactivation in malignant cells, surrounding immune cells and cancer-associated fibroblasts, mediates inhibition of the innate and adaptive immunity of the tumor microenvironment, and, therefore, tumor evasion from the immune system. These features highlight STAT3 as a promising therapeutic target; however, the mechanisms underlying these features have not been fully elucidated yet and STAT3 inhibitors have not reached the clinic in everyday practice. In the present article, we review the STAT3 signaling network in CRC and highlight the current notion for the design of STAT3-focused treatment approaches. We also discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, therefore providing a new perception for the clinical application of STAT3 in CRC.
Highlights
Colorectal cancer (CRC) represents one of the leading types of malignancy, in both genders, worldwide
We review the Signal transducer and activator of transcription 3 (STAT3) signaling network in CRC and highlight the current status for the development of STAT3-targeting treatment approaches
Corroborating findings in experiments with conditional ablation of STAT3 (Stat3∆IEC ApcMin/+ mice), show that STAT3 is activated during the initial stages of tumor development, but STAT3 negative regulation is needed for CRC tumor invasion [47]
Summary
Colorectal cancer (CRC) represents one of the leading types of malignancy, in both genders, worldwide. Most CRCs initiate from cancer stem cells (CSC)s inside the colonic epithelium, accumulating progressive genetic and epigenetic alterations These alterations lead to impaired gene expression and/or function, favoring the activation of oncogenes and the downregulation of tumor suppressor genes [2]. Targeted therapy and immunotherapy have aided in the configuration of more efficient patient selection criteria, regarding CRC treatment options, offering prolonged survival and increased progression-free survival for certain patient groups with distinct molecular characteristics [4]. In this context, transcription factors (TFs)—once referred to as “undruggable”— represent a unique class of drug targets. We discuss recent breakthroughs in combination immunotherapy regimens containing STAT3 inhibitors, offering new insight into the translational application of STAT3 in CRC [11]
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