Soluble Epidermal Growth Factor Receptors (sEGFRs) in Cancer: Biological Aspects and Clinical Relevance

Abstract

The identification of molecules that can reliably detect the presence of a tumor or predict its behavior is one of the biggest challenges of research in cancer biology. Biological fluids are intriguing mediums, containing many molecules that express the individual health status and, accordingly, may be useful in establishing the potential risk of cancer, defining differential diagnosis and prognosis, predicting the response to treatment, and monitoring the disease progression. The existence of circulating soluble growth factor receptors (sGFRs) deriving from their membrane counterparts has stimulated the interest of researchers to investigate the use of such molecules as potential cancer biomarkers. But what are the origins of circulating sGFRs? Are they naturally occurring molecules or tumor-derived products? Among these, the epidermal growth factor receptor (EGFR) is a cell-surface molecule significantly involved in cancer development and progression; it can be processed into biological active soluble isoforms (sEGFR). We have carried out an extensive review of the currently available literature on the sEGFRs and their mechanisms of regulation and biological function, with the intent to clarify the role of these molecules in cancer (and other pathological conditions) and, on the basis of the retrieved evidences, speculate about their potential use in the clinical setting.

Epidermal growth factor receptor detection in serum and saliva as a diagnostic and prognostic tool in oral cancer

“…Despite some reports showing increased values in affected patients, most studies (and those including a higher number of subjects) reported a decrease of serum EGFR in cancer patients, with a proportional impact on survival . This supports the hypothesis that serum EGFR could be a different isoform with a physiological and tumor‐protective role in the control of the EGFR‐regulated signaling . Similarly, we observed a reduction of serum EGFR in OSCC patients, but it was not possible to recognize any important impact on survival.…”

“…In our experience, saliva EGFR showed higher concentrations in OSCC patients compared with healthy controls, with a further increase in more advanced tumors (pT4 category) and a consequent impact on OS. In light of this, we can hypothesize that only saliva EGFR could be the tumor‐specific soluble isoform, whereas the serum‐circulating one could have a physiological role, as suggested for non–small cell lung cancer . The discrepancy in saliva EGFR performance between the present and Bernardes et al's studies may be due to the different ELISA kits used and the different saliva collection methods that can affect the composition of the saliva samples …”

“…[11][12][13][14][15][16]19,[29][30][31][32][33] Being a transmembrane receptor, the extracellular domain of EGFR can be released by proteolytic cleavage and shed from the surface of tumor cells or by mRNA alternative splicing, thus representing a potential tumor marker in biologic fluids. 34,35 Our data show a reduction of serum EGFR and an increase in saliva EGFR levels in OSCC patients compared with healthy controls. However, the difference in serum EGFR levels between the patient and healthy group should be further investigated, due to the impact of age on such a variable in our population.…”

“…Being a transmembrane receptor, the extracellular domain of EGFR can be released by proteolytic cleavage and shed from the surface of tumor cells or by mRNA alternative splicing, thus representing a potential tumor marker in biologic fluids . Our data show a reduction of serum EGFR and an increase in saliva EGFR levels in OSCC patients compared with healthy controls.…”

ERBB3: A potential serum biomarker for early detection and therapeutic target for devil facial tumour 1 (DFT1)

“…The use of serum ERBB’s as an indicator of human cancer appears useful however, its prognostic and theranostic value remains controversial and continued investigations will be required [81–96, 99]. The development of a diagnostic test for preclinical DFT1 would assist in the field operations if individuals could be identified before they become infectious[110], therefore application of serum ERBB3 as a diagnostic biomarker of DFT1 has great potential.…”