Group XIV C-type lectins: emerging targets in tumor angiogenesis

Abstract

C-type lectins, distinguished by a C-type lectin binding domain (CTLD), are an evolutionarily conserved superfamily of glycoproteins that are implicated in a broad range of physiologic processes. The group XIV subfamily of CTLDs are comprised of CD93, CD248/endosialin, CLEC14a, and thrombomodulin/CD141, and have important roles in creating and maintaining blood vessels, organizing extracellular matrix, and balancing pro- and anti-coagulative processes. As such, dysregulation in the expression and downstream signaling pathways of these proteins often lead to clinically relevant pathology. Recently, group XIV CTLDs have been shown to play significant roles in cancer progression, namely tumor angiogenesis and metastatic dissemination. Interest in therapeutically targeting tumor vasculature is increasing and the search for novel angiogenic targets is ongoing. Group XIV CTLDs have emerged as key moderators of tumor angiogenesis and metastasis, thus offering substantial therapeutic promise for the clinic. Herein, we review our current knowledge of group XIV CTLDs, discuss each's role in malignancy and associated potential therapeutic avenues, briefly discuss group XIV CTLDs in the context of two other relevant lectin families, and offer future direction in further elucidating mechanisms by which these proteins function and facilitate tumor growth.

Keywords: C-type lectin; Immunotherapy; Tumor angiogenesis; Vessel normalization.

Fig. 1

Structural representation of group XIV C-type lectin domain proteins in transmembrane state. CLEC14a, C-type lectin 14a, TM thrombomodulin

Fig. 2

Examples of anti-tumor therapeutic approaches targeting Group XIV CTLDs. a Monoclonal antibody (mAb) specifically targeting CTLD with either cellular depleting effects via antibody-dependent cell mediated cytotoxicity (ADCC) or blocking function inhibiting downstream signaling b Antibody drug conjugate (ADC) targeting CTLD to induce receptor mediated endocytosis of cytotoxic conjugate (CC) in form of DNA intercalators or inhibitors of cell division resulting in cell death c Anti-cancer vaccination with immunogen such as fused DNA construct of CTLD and tetanus toxoid stimulating CTLD specific cytotoxic T lymphocytes (CTLs) targeting malignant CTLD-expressing cells d Chimeric antigen receptor T (CAR T) cell therapy engineered with high specificity antibody binding fragments (V_H & V_L) targeting CTLD and intracellular T cell stimulating motifs to activate cytotoxicity via cytokines (interferon gamma). VEGF/R, vascular endothelial growth factor/receptor

Fig. 3

Summary of major interactions of group XIV C-type lectin domain protein family. Thrombomodulin (TM), CLEC14a, and CD93 are predominantly expressed on endothelial cells while CD248 is expressed on stromal cells and structural cells supporting vessels such as fibroblasts and pericytes, respectively. Fibronectin interacts with both TM and CD248 promoting stromal cell migration and adhesion; Multimerin-2 (MMRN2) interacts with CD248, CLEC14a, and CD93 to promote endothelial migration, adhesion, and vessel tube formation; Collagens I and IV interact with CD248 to maintain the extracellular matrix. FAK focal adhesion kinase, MMP9 matrix metalloprotease-9, APC activated protein C; HSP70-1a, heat shock protein-1a; VEGF/VEGFR, vascular endothelial growth factor (receptor), ERK extracellular signal-regulated kinase, PI3k/Akt phosphoinositide 3-kinase/protein kinase B, Cbl Casitas B cell lymphoma protooncogene, VE-C VE-cadherin, IGFBP7 insulin growth factor binding protein 7, PDGFR platelet derived growth factor receptor, PDGF-BB platelet derived growth factor-BB, SM22a transgelin