Secreted Frizzled-Related Protein 2 (SFRP2) is a secreted modulator, meaning it is produced by cells and released into the surrounding tissue environment to influence the behavior of neighboring cells. SFRP2 acts as a key regulator in fundamental biological processes that govern tissue maintenance, regeneration, and pathology. Its involvement in major health issues, ranging from chronic organ scarring (fibrosis) to aggressive malignancies, has positioned SFRP2 as a significant focus for new therapeutic development.
Defining SFRP2 and Its Normal Function
SFRP2 belongs to a family of soluble glycoproteins structurally similar to cell surface receptors that receive growth signals. Its function centers on modulating the Wnt signaling pathway, a master regulatory system in nearly all animal species. The Wnt pathway acts like a cellular “on/off” switch that tightly controls processes such as cell growth, division, and movement during development and tissue repair.
SFRP2 typically functions as an antagonist or “brake” for this pathway by physically binding to Wnt protein ligands secreted by other cells. By sequestering these ligands, SFRP2 prevents them from attaching to their primary Frizzled receptors on the cell surface, thereby downregulating the Wnt signal. However, SFRP2’s function is highly dependent on cellular context and local concentration. In some situations, especially at lower concentrations, SFRP2 can paradoxically act as an agonist, promoting Wnt signaling activity instead of inhibiting it.
SFRP2’s Role in Tissue Repair and Fibrosis
SFRP2 contributes to fibrosis, the excessive formation of scar tissue that leads to organ hardening and failure. SFRP2’s expression is significantly increased in tissues undergoing chronic injury, such as the heart after a myocardial infarction or in the lungs of patients with Idiopathic Pulmonary Fibrosis (IPF). In these contexts, SFRP2 activates fibroblasts, the primary cells responsible for generating scar tissue.
SFRP2 specifically promotes the accumulation of extracellular matrix (ECM) proteins, most notably collagen, which stiffens the tissue. It achieves this by enhancing the activity of procollagen C proteinase, an enzyme that converts procollagen into mature, insoluble collagen fibers. This mechanism accelerates the deposition of scar material. SFRP2 also drives scar formation by activating the canonical Wnt/\(\beta\)-catenin signaling pathway in cardiac and other organ fibroblasts. This activation promotes fibroblast proliferation and their transformation into myofibroblasts, the highly contractile, scar-producing cells, leading to maladaptive repair.
SFRP2 and Cancer Development
SFRP2 exhibits a complex, context-dependent role in cancer, acting as either a tumor suppressor or a tumor promoter depending on the type of malignancy. Its function is often determined by the specific genetic and epigenetic landscape of the tumor cell. This dual nature makes SFRP2 a challenging but promising target in oncology.
In several cancers, including colorectal cancer, gastric cancer, and some gliomas, SFRP2 acts as a tumor suppressor. In these cases, the gene for SFRP2 is often silenced or inactivated through promoter hypermethylation. The loss of SFRP2 removes the “brake” on the canonical Wnt signaling pathway, allowing the pathway to become hyperactive and drive uncontrolled cell proliferation. Restoring SFRP2 function in these tumors can suppress tumor growth and invasion.
Conversely, in other malignancies like renal cell carcinoma, angiosarcoma, and certain aggressive breast cancers, SFRP2 is overexpressed and actively promotes tumor progression. SFRP2 contributes to the tumor’s survival and metastatic capacity, often by activating the non-canonical Wnt signaling pathways. SFRP2 can also directly enhance angiogenesis, the formation of new blood vessels, by activating the calcineurin/NFATc3 pathway in endothelial cells.
Developing Treatments Targeting SFRP2
Researchers are actively developing therapeutic strategies aimed at modulating SFRP2 activity due to its involvement in both fibrosis and cancer progression. The primary approach focuses on inhibition, particularly for diseases where SFRP2 is overexpressed and acts as a promoter. This strategy involves creating highly specific monoclonal antibodies or small molecules designed to neutralize the SFRP2 protein in the extracellular space.
In the context of fibrosis, anti-SFRP2 antibodies are being investigated to block the protein’s ability to activate fibroblasts and enhance collagen production. Early studies have shown that blocking SFRP2 can reduce cardiac scarring and promote beneficial tissue remodeling after injury.
For cancers where SFRP2 acts as an oncogene, such as angiosarcoma and triple-negative breast cancer, antibodies against SFRP2 have demonstrated the ability to inhibit tumor growth and metastasis in preclinical models. By neutralizing SFRP2, these therapies aim to disrupt the non-canonical Wnt signaling and suppress tumor angiogenesis. For cancers where SFRP2 is silenced, researchers are exploring compounds that could reverse the epigenetic silencing, restoring SFRP2’s function as a Wnt inhibitor and tumor suppressor.