Abstract
Hepatocellular carcinoma (HCC) is the most common primary malignancy of the liver and a leading cause of death in the US and worldwide. HCC remains a global health problem and is highly aggressive with unfavorable prognosis. Even with surgical interventions and newer medical treatment regimens, patients with HCC have poor survival rates. These limited therapeutic strategies and mechanistic understandings of HCC immunopathogenesis urgently warrant non-palliative treatment measures. Irrespective of the multitude etiologies, the liver microenvironment in HCC is intricately associated with chronic necroinflammation, progressive fibrosis, and cirrhosis as precedent events along with dysregulated innate and adaptive immune responses. Central to these immunological networks is the complement cascade (CC), a fundamental defense system inherent to the liver which tightly regulates humoral and cellular responses to noxious stimuli. Importantly, the liver is the primary source for biosynthesis of >80% of complement components and expresses a variety of complement receptors. Recent studies implicate the complement system in liver inflammation, abnormal regenerative responses, fibrosis, carcinogenesis, and development of HCC. Although complement activation differentially promotes immunosuppressive, stimulant, and angiogenic microenvironments conducive to HCC development, it remains under-investigated. Here, we review derangement of specific complement proteins in HCC in the context of altered complement regulatory factors, immune-activating components, and their implications in disease pathogenesis. We also summarize how complement molecules regulate cancer stem cells (CSCs), interact with complement-coagulation cascades, and provide therapeutic opportunities for targeted intervention in HCC.
Highlights
Specialty section: This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology
Results from the analysis identified a combination of C4b-Binding Protein (C4BP), LRG1, and SAA or C4BP alone as determinants of disease prognosis, treatment optimization, and overtreatment prevention in patients with non-small cell lung cancer (NSCLC) [281]
The worldwide prevalence, lack of available therapeutic modalities, and rapid progression to severely compromised liver functions urgently necessitate identification and interrogation of newer mechanisms towards better treatment approaches. This urgent need is dictated by the only available treatment of Hepatocellular carcinoma (HCC) that relies on liver transplantation, which inherently suffers from shortage of donor livers, higher costs, risk of tumor recurrence, etc
Summary
Specialty section: This article was submitted to Gastrointestinal Cancers, a section of the journal Frontiers in Oncology. Associations of the CXCL12–CXCR4 pathway in supporting metastasis and disease severity have been demonstrated using HCC cell lines, showing increased MMP2 and MMP9 secretion [84] and decreased 3-year-survival rates in patients [85]. High levels of CXCR4expressing OV6+ tumor-initiating cells in HCC patient livers are associated with aggressive pathobiology, increased invasion, metastasis, and poor prognosis [90].
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
