C4.4A as a candidate marker in the diagnosis of colorectal cancer

Abstract

C4.4A is a member of the Ly-6 family with restricted expression in non-transformed tissues. C4.4A expression in human cancer has rarely been evaluated. Thus, it became important to explore C4.4A protein expression in human tumour tissue to obtain an estimate on the frequency of expression and the correlation with tumour progression, the study focusing on colorectal cancer. The analysis of C4.4A in human tumour lines by western blot and immunoprecipitation using polyclonal rabbit antibodies that recognize different C4.4A epitopes revealed C4.4A oligomer and heavily glycosylated C4.4A isoform expression that, in some instances, inhibited antibody binding and interaction with the C4.4A ligand galectin-3. In addition, tumour cell lines released C4.4A by vesicle shedding and proteolytic cleavage. C4.4A was expressed in over 80% of primary colorectal cancer and liver metastasis with negligible expression in adjacent colonic mucosa, inflamed colonic tissue and liver. This compares well with EpCAM and CO-029 expression in over 90% of colorectal cancer. C4.4A expression was only observed in about 50% of pancreatic cancer and renal cell carcinoma. By de novo expression in colonic cancer tissue, we consider C4.4A as a candidate diagnostic marker in colorectal cancer, which possibly can be detected in body fluids.

Expression of C4.4A, a Structural uPAR Homolog, Reflects Squamous Epithelial Differentiation in the Adult Mouse and during Embryogenesis

“…C4.4A was initially identified as a metastasis-associated protein (Claas et al 1996), and expression of C4.4A is accordingly observed in various human cancer lesions Hansen et al 2007;Paret et al 2007;Smith et al 2001;Würfel et al 2001). In NSCLC, its expression levels even carry prognostic information on patient survival ).…”

New Blocking Antibodies against Novel AGR2–C4.4A Pathway Reduce Growth and Metastasis of Pancreatic Tumors and Increase Survival in Mice

“…Similar to Prod-1, C4.4A belongs to the Ly6 family of receptors including CD59 (13) and uPAR (19) and was associated with increased metastasis of PDAC (20,21) melanoma (22) and non-small cell lung cancer (23). AGR2 protein levels are correlated with poor prognosis in breast cancer (23) and colorectal cancer (24,25) Furthermore, like other glycosylphosphatidylinositol (GPI)-linked plasma membrane receptors, C4.4A lacks intracellular domains to mediate its downstream signaling. To date, the signaling mechanisms engaged by C4.4A have not been identified.…”

Preclinical Antitumor Efficacy of BAY 1129980—a Novel Auristatin-Based Anti-C4.4A (LYPD3) Antibody–Drug Conjugate for the Treatment of Non–Small Cell Lung Cancer

“…On the transcriptional level, approximately 50% of primary lung cancers and 75% of lung cancer metastases express C4.4A mRNA, whereas no expression has been detected in normal lung tissue (12,13). In addition, C4.4A is expressed in colorectal (6,14,15) and breast cancer (16).…”

“…It was first described as a metastasis-associated cell surface protein in rat pancreatic tumor cells (2) and since then, has been associated with carcinogenesis in several different cancers (3)(4)(5). In cancer, C4.4A has been suggested to be involved specifically in tumor cell invasion via interaction with the extracellular matrix (2,6). C4.4A is strongly overexpressed in non-small cell lung cancer (NSCLC) with preferential expression in squamous cell carcinoma (SCC) subtype compared with the other two most common NSCLC subtypes; adenocarcinoma (AC) and large-cell carcinoma (LCC) (4,5,7,8).…”