Complement factor H in cancer biology: intracellular functions, tumor-host interactions, and systemic context

Area of Science:

• Immunology
• Molecular Biology
• Oncology

Background:

• Complement factor H (FH) is a key regulator of the alternative complement pathway.
• Beyond its extracellular functions, intracellular FH influences cancer-related signaling pathways like p53/NF-κB and cytoskeletal organization.
• Tumor-associated FH can be targeted by antibodies, impacting therapeutic strategies.

Purpose of the Study:

• To propose a framework that distinguishes systemic FH availability from local intracellular and extracellular functions.
• To highlight the distinct roles of different FH pools (intracellular, soluble, surface-associated, extracellular-vesicle-associated).
• To emphasize the need for compartment-resolved analyses of FH in cancer research and biomarker development.

Main Methods:

• Review and synthesis of existing literature on FH functions in cancer.
• Distinguishing between nuclear and cytosolic FH interactions and their associated cellular processes.
• Analysis of FH's role at the tumor-host interface and its interaction with immune cells.
• Consideration of FH's presence in various cellular compartments and its implications.

Main Results:

• FH exhibits diverse intracellular roles, including involvement in p53/NF-κB signaling, cell-cycle regulation, and actin organization.
• Extracellular FH protects tumor cells and vesicles from complement-mediated damage and influences immune cell programs.
• Structurally altered FH can be recognized by endogenous antibodies and targeted by therapeutic antibodies like GT103.
• FH exists in distinct pools (intracellular, soluble, surface-associated, extracellular-vesicle-associated) with non-interchangeable functions.

Conclusions:

• A source- and compartment-resolved framework is proposed to better understand FH's multifaceted roles in cancer.
• Local intracellular and extracellular FH functions are distinct from systemic FH availability.
• Further research requires tissue-specific models and paired measurements to elucidate FH's complex biology and therapeutic potential.