Dr Yang Wang and colleagues from Vanderbilt University have shown a novel mechanism of cancer development through EGFR negative regulator, LRIG1.
LRIG1 negatively regulates EGFR signaling. Image credit: Yang Wang et al.
Stem cells are responsible for tissue proliferation and regeneration. Intestinal epithelium, a single layer of cells lining the intestine that separate external and internal environment, is a highly regenerative tissue, with old cells replaced by new ones every 4-6 days.
Stem cells play an important role in maintaining intestinal homeostasis by replenishing dead and sloughed off cells. Epidermal growth factor receptor (EGFR), as the name suggests, provides proliferative signaling to the intestinal epithelium and helps maintain homeostasis.
EGFR signaling, however, needs to be tightly controlled. Insufficient EGFR signaling is the cause of neurodegenerative disorders and also results in developmental defects in mice. On the other hand, excessive EGFR signaling is critical to a number of malignancies. For example, overexpression of EGFR is associated with metastatic colon cancer.
One mechanism of control of EGFR signaling is through its negative regulator, LRIG1. Recently, it was also shown that LRIG1 marks stem cells of the large intestine. LRIG1 was proposed to be a tumor suppressor for almost a decade; only recently have scientists found direct genetic evidence for LRIG1 being a tumor suppressor.
The review, published in British Journal of Cancer, describes the three critical and interrelated roles of LRIG1 in intestinal physiology of being a tumor suppressor, EGFR negative regulator, and a stem cell marker.
Lead author Dr Yang Wang from the lab of Prof Robert Coffey at Vanderbilt University with co-authors begin the review discussing our current understanding of the role of LRIG1 in regulating EGFR signaling.
Then, they systematically review the in vivo evidence supporting LRIG1 being a tumor suppressor. Loss of tumor suppressors usually leads to early onset of cancer; genetic ablation of LRIG1 in mice also results in spontaneous duodenal adenoma at a young age.
No significant LRIG1 mutations have been found in human cancers. Thus, Dr Wang and colleagues reviewed the literature and mined published dataset regarding expression of LRIG1 in human cancer. In this analysis, the authors showed the loss of LRIG1 in cancer. In addition, LRIG1 expression largely correlated positively with cancer prognosis, further supporting its role as tumor suppressor. A senior graduate student Emily J Poulin in the lab of Prof Robert J Coffey co-authored the study.
Recently, progress has been made addressing the therapeutic potential of LRIG1. Soluble extracellular portion of LRIG1 has been shown to inhibit human glioma growth in mouse xenografts.
Therefore, targeting restoration of LRIG1 may be a promising anticancer strategy.
______
Yang Wang, Emily J Poulin, & Robert J Coffey. 2013. LRIG1 is a triple threat: ERBB negative regulator, intestinal stem cell marker and tumour suppressor. British Journal of Cancer, 108: 1765-70; doi: 10.1038/bjc.2013.138
