The EFEMP1 gene provides instructions for making a protein also known as Fibulin-3. This protein is a member of the fibulin family, which are secreted glycoproteins. Fibulin-3 is found throughout the body, particularly within the extracellular matrix. The extracellular matrix acts like a complex scaffolding or mortar that holds cells together and provides structural support to tissues.
It is broadly expressed in both developing and adult tissues, particularly in epithelial and endothelial cells. Within this network, it influences various cellular behaviors and functions.
The Normal Role of EFEMP1 in the Body
The EFEMP1 protein plays a part in maintaining the structural integrity of various tissues. It helps connect and integrate partner molecules within the extracellular matrix. This role is particularly evident in its contribution to the integrity of basement membrane zones, which are specialized layers of the extracellular matrix that provide support to cells.
Fibulin-3 also aids in anchoring other extracellular matrix structures, such as elastic fibers, to basement membranes. Beyond its structural contributions, EFEMP1 modulates cellular behavior. It influences cell adhesion, helping cells attach to each other and to their surrounding matrix. Additionally, it participates in regulating cell growth and proliferation.
The Link Between EFEMP1 and Age-Related Diseases
Mutations in the EFEMP1 gene are directly linked to specific inherited eye conditions, particularly Doyne honeycomb retinal dystrophy (DHRD), also known as Malattia Leventinese. This autosomal dominant disorder is characterized by the early development of yellow-white deposits called drusen, which accumulate beneath the retinal pigment epithelium. These drusen often appear in a radial or “honeycomb” pattern around the macula and optic nerve head.
A specific mutation, R345W, in EFEMP1 has been identified in families with DHRD. While wild-type EFEMP1 is typically secreted, the mutant protein can become misfolded and inefficiently secreted, leading to its retention within cells. In individuals with DHRD or age-related macular degeneration (AMD), EFEMP1 accumulates beneath the retinal pigment epithelium, often overlaying drusen.
This aberrant accumulation of dysfunctional EFEMP1 is thought to contribute to drusen formation and cellular degeneration, playing a role in the progression of both DHRD and AMD. The clinical features of DHRD, including drusen formation and subsequent vision impairment, closely resemble those seen in age-related macular degeneration, which is a major cause of vision loss in older adults. The protein’s involvement also broadly connects to “inflammaging,” a chronic, low-grade inflammation that is a hallmark of the aging process.
The Complex Role of EFEMP1 in Cancer
The EFEMP1 protein exhibits a dual and often opposing role in cancer progression, acting as both a tumor suppressor and, in other contexts, a promoter of tumor growth. Its function is highly dependent on the specific type of cancer and the cellular environment. This makes understanding its role in cancer particularly intricate.
In some cancers, such as breast, lung, and endometrial carcinomas, EFEMP1 functions as a tumor suppressor. In these cases, its expression is often downregulated. When functioning as a tumor suppressor, EFEMP1 can inhibit cancer cell proliferation, invasion, and migration, thereby slowing tumor progression. For example, in non-small cell lung cancer, EFEMP1 suppresses tumor growth and invasion.
In other cancer types, however, EFEMP1 can promote tumor progression and invasion. It is highly expressed in malignant gliomas, where it contributes to the aggressive nature of these brain tumors. In glioblastoma, EFEMP1 can enhance cell adhesion and promote cell motility and dispersion. Similarly, in ovarian carcinoma and malignant pleural mesothelioma, increased EFEMP1 expression is associated with tumor progression, increased cell viability, and enhanced invasion. In these contexts, EFEMP1 can activate signaling pathways that contribute to the malignant behavior of cancer cells.
Current Research and Therapeutic Implications
Scientists are actively exploring the practical applications of understanding EFEMP1’s diverse roles, particularly its potential as a biomarker. Levels of EFEMP1 protein or its gene expression are being investigated for their utility in diagnosing certain diseases or predicting patient outcomes. For instance, EFEMP1 levels in serum have shown promise in distinguishing osteosarcoma patients from healthy individuals and may indicate lung metastasis. In malignant pleural mesothelioma, EFEMP1 accumulation in pleural effusions is considered a prognostic biomarker.
Current therapeutic strategies being researched largely depend on whether EFEMP1 is acting beneficially or harmfully in a given disease. For cancers where EFEMP1 promotes tumor growth, such as malignant pleural mesothelioma, efforts are focused on developing ways to block its activity. This includes exploring the use of function-blocking antibodies that can inhibit EFEMP1 signaling and reduce tumor progression.
In diseases where EFEMP1 deficiency or dysfunction is the problem, such as certain forms of eye disease or cancers where it acts as a tumor suppressor, research aims to restore or supplement its function. These approaches are still in the early stages of investigation. It is important to remember that these strategies are areas of active scientific inquiry and are not yet established as standard treatments available to patients.