Adhesion receptors as therapeutic targets for circulating tumor cells

Abstract

Metastasis contributes to >90% of cancer-associated mortality. Though primary tumors can be removed by surgical resection or chemo/radiotherapy, metastatic disease is a great challenge to treatment due to its systemic nature. As metastatic "seeds," circulating tumor cells (CTCs) are believed to be responsible for dissemination from a primary tumor to anatomically distant organs. Despite the possibility of physical trapping of CTCs in microvessels, recent advances have provided insights into the involvement of a variety of adhesion molecules on CTCs. Such adhesion molecules facilitate direct interaction with the endothelium in specific tissues or indirectly through leukocytes. Importantly, significant progress has been made in understanding how these receptors confer enhanced invasion and survival advantage during hematogenous circulation of CTCs through recruitment of macrophages, neutrophils, platelets, and other cells. This review highlights the identification of novel adhesion molecules and how blocking their function can compromise successful seeding and colonization of CTCs in new microenvironment. Encouraged by existing diagnostic tools to identify and isolate CTCs, strategic targeting of these adhesion molecules to deliver conventional chemotherapeutics or novel apoptotic signals is discussed for the neutralization of CTCs in the circulation.

Keywords: CTCs; adhesion; cancer therapy; receptors.

Figure 1

The heterotypic cell interactions between CTCs and haemopotoeic cells in the circulation. Macrophages interact with CTCs via α4-integrin-VCAM-1 ligation and transmit anti-apoptotic signal such as TRAIL to CTCs. In contrast, certain CTCs deficient for selectin ligands can roll and adhere to endothelial cells through heterotypic interaction with neutrophils. This interaction is mediated by β2-integrin and ICAM-1 expressed on neutrophils and CTCs, respectively. Additionally, CTCs can locally induce platelet aggregation. The deposition of platelets on CTCs prevents the damage caused by shear stress and immuno-surveillance.

Figure 2

E-selectin liposomal and nanotube-targeted delivery of doxorubicin to CTCs. (A) Schematic of E-selectin-coated liposome encapsulating doxorubicin (DOX). (B) Schematic of a microtube device for delivering DOX to captured CTCs.

Figure 3

Delivery of apoptotic signal to rolling cancer cells. (A) Schematic of a biomimetic device for inducing apoptosis in CTCs using E-selectin and TRAIL. (B) HL60 leukemic cells are eliminated by approximately 30% following perfusion through a device coated with both E-selectin and TRAIL. (C) Viability of normal mononuclear cells is not affected by the TRAIL-coating, confirming the specificity of TRAIL for malignant cells. (A–C) are reproduced from Rana et al., with permission. Rana et al., is Copyright 2008 Wiley Periodicals, Inc.).