Stromal Targets for Fluorescent-Guided Oncologic Surgery

Abstract

Pre-operative imaging techniques are essential for tumor detection and diagnosis, but offer limited help during surgery. Recently, the applicability of imaging during oncologic surgery has been recognized, using near-infrared fluorescent dyes conjugated to targeting antibodies, peptides, or other vehicles. Image-guided oncologic surgery (IGOS) assists the surgeFon to distinguish tumor from normal tissue during operation, and can aid in recognizing vital structures. IGOS relies on an optimized combination of a dedicated fluorescent camera system and specific probes for targeting. IGOS probes for clinical use are not widely available yet, but numerous pre-clinical studies have been published and clinical trials are being established or prepared. Most of the investigated probes are based on antibodies or peptides against proteins on the membranes of malignant cells, whereas others are directed against stromal cells. Targeting stroma cells for IGOS has several advantages. Besides the high stromal content in more aggressive tumor types, the stroma is often primarily located at the periphery/invasive front of the tumor, which makes stromal targets particularly suited for imaging purposes. Moreover, because stroma up-regulation is a physiological reaction, most proteins to be targeted on these cells are "universal" and not derived from a specific genetic variation, as is the case with many upregulated proteins on malignant cancer cells.

Keywords: cancer; imaging; stroma; surgery; targeting; tumor-associated.

Figure 1

Histological representation of targetable stromal cells. Immunohistochemical analyses of a ductal breast carcinoma. (I, SMA) Cancer-associated fibroblasts (CAF) are disperse located through the whole tumor. The endothelial cells captured in (II, CD31) are mainly neo-angiogenic as seen in (III, CD105). (IV, DC68) Most of the macrophages present in this tumor consist of the M2 type (V, CD163). Picture (VI, CD45) shows lymphocytes that are located in conglomerates on the tumor border. AT, adipose tissue.

Figure 2

Schematic representation of stromal cells in a ductal adenocarcinoma. Overview of the location of the various stromal cells that can be targeted for imaging. Infiltrating immune cells are mainly located in the periphery, creating a rim around the tumor, and in necrotic areas. Neo-angiogenic endothelial cells are primarily present at the invasive front. Cancer-associated fibroblasts are mainly recognized in proximity and between malignant cells, whereas normal (myo)fibroblasts are dispersed throughout the extracellular matrix, providing rigidity and strength. Necrotic areas are mostly recognized in the tumor core.