Altered expression of the urokinase receptor homologue, C4.4A, in invasive areas of human esophageal squamous cell carcinoma

Abstract

C4.4A is a glycolipid-anchored membrane protein with structural homology to the urokinase-type plasminogen activator receptor (uPAR). Although C4.4A was identified as a metastasis-associated protein little is known about its actual expression and possible function in malignant disease. In the present study, we have therefore analyzed the expression of C4.4A in 14 esophageal squamous cell carcinomas (ESCC). Normal squamous esophageal epithelium shows a strong cell surface associated C4.4A expression in the suprabasal layers, whereas basal cells are negative. Upon transition to dysplasia and carcinoma in situ the expression of C4.4A is abruptly and coordinately weakened. Double immunofluorescence staining of normal and dysplastic tissue showed that C4.4A colocalizes with the epithelial cell surface marker E-cadherin in the suprabasal cells and has a complementary expression pattern compared to the proliferation marker Ki-67. A prominent, but frequently intracellular, C4.4A expression reappeared in tumor cells located at the invasive front and local lymph node metastases. Because C4.4A was reported previously to be a putative laminin-5 (LN5) ligand, and both proteins are expressed by invasive tumor cells, we analyzed the possible coexpression of C4.4A and the c2-chain of LN5 (LN5-c2). Although these proteins are indeed expressed by either neighboring cancer cells or in a few cases even coexpressed by the same cells in the tumor front and metastases, we found no evidence for a general colocalization in the extracellular compartment by confocal microscopy. In conclusion, C4.4A is expressed during invasion and metastasis of human ESCC and may thus provide a new histological marker in this disease. ' 2007 Wiley-Liss, Inc.Key words: laminin-5; invasion; metastasis; microenvironment; uPAR Patients diagnosed with esophageal squamous cell carcinoma (ESSC) have a very poor prognosis.1 The explanation for the severe clinical behavior of this cancer is found in its extremely aggressive invasive character, despondently reflected by the 10% 5-year survival rate.2 In the majority of ESCC patients the cancer has already invaded the underlying muscle at the time of diagnosis, and in more than 50% of the cases the cancer cells have formed distant metastases.3,4 Because invasion and metastasis are considered major prognostic determinants in ESCC, there is a great interest in elucidating the mechanisms behind these processes.1 Activation of extracellular proteases and alterations in the binding abilities and expression of cell adhesion molecules (CAMs) are well-consolidated events in cancer cell dissemination, but more information at the molecular level is needed in order to develop intervention strategies and refine prognostic evaluations. 5-7A significant focus on identifying and investigating various new molecules as potential prognostic and diagnostic markers of cancer invasion and metastasis has developed during the last decade. C4.4A is an example of such a molecule. 8,9 This protein is a close relative of the urokinase-type p...

Altered LKB1/CREB-regulated transcription co-activator (CRTC) signaling axis promotes esophageal cancer cell migration and invasion

“…In the adjacent normal mucosa's squamous epithelium, there was strong LYPD3 staining in the cell membranes of differentiated cells, but no staining in the basal cell compartment (Figure 6g), which is consistent with previous staining data (Hansen et al, 2008). On the other hand, we found that LYPD3 is overexpressed in various stages of cancer development, including carcinoma in situ and carcinoma at more advanced stages.…”

“…The exact biochemical functions of LYPD3 are unknown; however, it was shown to interact with the adhesion proteins laminin-1, laminin-5 and galectin-3, which might promote metastasis and matrix invasion (Paret et al, 2005). With regard to esophageal cancer, LYPD3 was proposed as a histological marker of invasion and metastasis for ESCC (Hansen et al, 2008). Our data extend the finding that LYPD3 is overexpressed in a high percentage of ESCCs, suggesting an important role in ESCC development.…”

“…LYPD3 is upregulated in metastasizing tumor cells, but showed restricted expression in normal adult tissues (Rosel et al, 1998;Seiter et al, 2001;Wurfel et al, 2001;Hansen et al, 2008). The exact biochemical functions of LYPD3 are unknown; however, it was shown to interact with the adhesion proteins laminin-1, laminin-5 and galectin-3, which might promote metastasis and matrix invasion (Paret et al, 2005).…”

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

“…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).…”

“…Overexpression of C4.4A has also been detected in SCC of the head and neck (HNSCC) including esophageal SCC (ESCC) subtype (3,11). 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).…”