Abstract
Squamous cell carcinoma (SCC) accounts for the majority of non-melanoma skin cancer related deaths, particularly in immunosuppressed persons. Identification of biomarkers that could be used to identify or treat SCC would be of significant benefit. The anthrax toxin receptors, Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2), are endothelial receptors involved in extracellular matrix homeostasis and angiogenesis that are selectively upregulated on numerous tumors. One method of targeting these receptors is Protective Antigen (PA), a protein produced by B. anthracis that mediates binding and translocation of anthrax toxins into cells. PA targeted toxins have been demonstrated to selectively inhibit tumor growth and angiogenesis, but tumor selectivity of PA is currently unknown. In this work fluorescently labeled PA was shown to maintain receptor dependent binding and internalization in vitro. Utilizing a human papillomavirus transgenic mouse model that develops cutaneous SCC in response to ultraviolet irradiation we identified tumor uptake of PA in vivo. The intravenously administered PA resulted in tumor specific localization, with exclusive tumor detection 24 h post injection. Ex vivo analysis identified significantly higher fluorescence in the tumor compared to adjacent healthy tissue and major clearance organs, demonstrating low non-specific uptake and rapid clearance. While both TEM8 and CMG2 were observed to be overexpressed in SCC tumor sections compared to control skin, the intravenously administered PA was primarily co-localized with TEM8. These results suggest that PA could be systemically administered for rapid identification of cutaneous SCC, with potential for further therapeutic development.
Highlights
Non-melanoma skin cancer (NMSC) has the highest incidence rate of all cancers, higher than all other cancers combined [1]
Protective Antigen (PA), a protein produced by B. anthracis, has been demonstrated to be a potential option for targeted delivery of drug molecules [7] or toxins [8] to tumors
PA is a component of the anthrax toxin facilitating the translocation of toxin enzymes into the cytosol through highly specific and selective interactions with two highly conserved anthrax toxin receptors known as Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2) [9]
Summary
Non-melanoma skin cancer (NMSC) has the highest incidence rate of all cancers, higher than all other cancers combined [1]. PA is a component of the anthrax toxin facilitating the translocation of toxin enzymes into the cytosol through highly specific and selective interactions with two highly conserved anthrax toxin receptors known as Tumor Endothelial Marker 8 (TEM8) and Capillary Morphogenesis Gene 2 (CMG2) [9]. TEM8 and CMG2 are endothelial cell surface receptors involved in extracellular matrix (ECM) homeostasis [10, 11] and angiogenesis [12, 13] that exhibit differential expression in healthy and tumor tissues. CMG2 is involved in endothelial cell proliferation [12], adhesion [22], capillary formation in vitro [23], and collagen VI homeostasis in vivo [24]. The expression of the anthrax toxin receptors in tumors may inform on pathological changes to the ECM involved in angiogenesis, invasiveness, and metastatic potential
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