Leucine-rich Alpha-2-glycoprotein-1 and Its Binding Partners, Cytochrome c and Transforming Growth Factor-b1, Promote Cancer Progression in an Apoptotic Microenvironment
Author(s): Professor. Ronald Jemmerson
Leucine-rich alpha-2-glycoprotein-1 (LRG1) is an acute-phase protein which increases in circulation when the immune system responds to tissue damage, certain microbial infections, and cancer. In the apoptotic microenvironment of a tumor, cytochrome c (Cyt c), along with other damage-associated molecular patterns (DAMPs), is released from dying cells. LRG1, also produced by cancer cells, binds Cyt c with high affinity and delays the onset of extracellular Cyt c-induced apoptosis and blocks its pro-inflammatory effects. Extracellular LRG1 has been shown to signal through epidermal growth factor (EGF) family of receptors to alter the expression of proteins that regulate the release of Cyt c from mitochondria and, thereby, inhibit apoptosis. Activation of a set of transcription factors via this pathway also promotes proliferation of cancer cells and their migration. Signaling through the transforming growth factor (TGF) receptor on endothelial cells, LRG1 complexed with endoglin and another binding partner, TGF-b1, plays a key role in neovascularization of tumors. This results in dysfunctional and leaky blood vessels which hinder the delivery of chemotherapeutic drugs to tumors and support cancer cell extravasation to other tissues. TGF-b1 is released from cells of the immune system in response to apoptotic signals including the exposure of phosphatidylserine (PS) on apoptotic cells and blebs. Potential therapeutic approaches to reduce the effects of LRG1 in pre-clinical testing include a humanized monoclonal antibody (mAb) and a proteolysis targeting chimera (PROTAC) to degrade cytoplasmic LRG1. LRG1 and its binding partners, Cyt c and TGF-b1, provide further insight into the progression of cancer that paradoxically occurs in an apoptotic environment during chemotherapy.