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.
The molecular mechanism of circadian clocks depends on transcription-translation feedback loops (TTFLs) that have known effects on key cellular processes. However, the distinct role of circadian TTFLs in mammalian stem cells and other less differentiated cells remains poorly understood. Neural stem cells (NSCs) of the brain generate neurons and glia postnatally but also may become cancer stem cells (CSCs), particularly in astrocytomas. Evidence indicates clock TTFL impairment is needed for tumor growth and progression; although, this issue has been examined primarily in more differentiated cancer cells rather than CSCs. Similarly, few studies have examined circadian rhythms in NSCs. After decades of research, it is now well recognized that tumors consist of CSCs and a range of other cancer cells along with noncancerous stromal cells. The circadian properties of these many contributors to tumor properties and treatment outcome are being widely explored. New molecular tools and ones in development will likely enable greater discrimination of important circadian and non-circadian cells within malignancies at multiple stages of cancer progression and following therapy. Here, we focus on adult NSCs and glioma CSCs to address how cells at different stages of differentiation may harbor unique states of the molecular circadian clock influencing differentiation and cell fate.
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