The Sialomucin CD34 Is a Marker of Lymphatic Endothelial Cells in Human Tumors

Abstract

The mechanisms of lymphangiogenesis have been increasingly understood in recent years. Yet, the contribution of lymphangiogenesis versus lymphatic cooption in human tumors and the functionality of tumor lymphatics are still controversial. Furthermore, despite the identification of lymphatic endothelial cell (LEC) markers such as Prox1, podoplanin, LYVE-1, and VEGFR-3, no activation marker for tumor-associated LECs has been identified. Applying double-staining techniques with established LEC markers, we have screened endothelial cell differentiation antigens for their expression in LECs. These experiments identified the sialomucin CD34 as being exclusively expressed by LECs in human tumors but not in corresponding normal tissues. CD34 is expressed by LYVE-1(+)/podoplanin(+)/Prox1(+) tumor-associated LECs in colon, breast, lung, and skin tumors. More than 60% of analyzed tumors contained detectable intratumoral lymphatics. Of these, more than 80% showed complete co-localization of CD34 with LEC markers. In contrast, LECs in all analyzed normal organs did not express CD34. Corresponding analyses of experimental tumors revealed that mouse tumor-associated LECs do not express CD34. Taken together, these experiments identify CD34 as the first differentially expressed LEC antigen that is selectively expressed by tumor-associated LECs. The data warrant further exploration of CD34 in tumor-associated LECs as a prognostic tumor marker.

CCL21 Expression Pattern of Human Secondary Lymphoid Organ Stroma Is Conserved in Inflammatory Lesions with Lymphoid Neogenesis

“…They also were CD31 ϩ31,32 and displayed variable levels of CD34, a pan-vascular marker that is often absent from normal tissue lymphatics but can be up-regulated in certain pathological conditions, such as in tumor-associated lymphangiogenesis. 44 The combinatorial phenotype that we report here clearly indicates the lymphatic nature of CCL21 ϩ vascular structures. In keeping with this, we demonstrated that synovial CCL21 ϩ lymphatics can express variable levels of D6, a lymphatic promiscuous chemokine receptor that functions as a scavenger receptor for the internalization and neutralization of inflammatory chemokines.…”

Lymphatic endothelial cell identity is reversible and its maintenance requires Prox1 activity

“…In angiosarcomas, intratumoral capillaries express a mixed blood/lymphatic phenotype (BreitenederGeleff et al 1999), and highly proliferative lymphatic vessels within tumors express CD34, a BEC surface antigen not expressed by normal adult lymphatics (Fiedler et al 2006). In Kaposi sarcoma, BEC to LEC switches have been reported and spindle cells have been shown to express LEC and BEC markers (Hong et al 2004;Wang et al 2004).…”

The New Era of the Lymphatic System: No Longer Secondary to the Blood Vascular System

“…Although exclusively expressed in BECs in normal tissue, ESAM was up-regulated in tumor lymphatics and linked with nodal metastasis (Clasper et al 2008). Moreover, another BEC-signature molecule, CD34, was reported to be expressed by tumor-associated LECs in colon, breast, lung, and skin tumors, and a majority of intratumoral lymphatics revealed a complete colocalization of CD34 with various LEC markers such as LYVE-1, podoplanin, and Prox1 (Fiedler et al 2006). …”