Breast tumor microenvironment: proteomics highlights the treatments targeting secretome

Abstract

Tumor secreted substances (secretome), including extracellular matrix (ECM) components, act as mediators of tumor-host communication in the breast tumor microenvironment. Proteomic analysis has emphasized the value of the secretome as a source of prospective markers and drug targets for the treatment of breast cancers. Utilizing bioinformatics, our recent studies revealed global changes in protein expression after the activation of ECM-mediated signaling in breast cancer cells. A newly designed technique integrating a capillary ultrafiltration (CUF) probe with mass spectrometry was demonstrated to dynamically sample and identify in vivo and pure secretome from the tumor microenvironment. Such in vivo profiling of breast cancer secretomes may facilitate the development of novel drugs specifically targeting secretome.

Figure 1

Sampling tumor secretome in vivo via a CUF probe. A CUF probe can be implanted into a growing tumor mass. The implanted probe collects the in vivo tumor secretome released either from tumor cells (T) or nontumor cells (N). The CUF probe extracts tumor secretome by using a vacuum applied to semipermeable hollow membrane fiber (a). The vacuum can be created by withdrawing a syringe from the vacutainer (V). The extraction efficiency of the CUF probe relies on the various pore sizes and surface charges of membrane fibers as well as the nature of proteins/peptides. As a general rule, large sizes of proteins/peptides are retained, while small proteins/peptides pass through the membrane. The CUF probes can be fabricated to fit the various sizes of tumor masses. The semipermeable hollow membrane fiber at the front end of the probe is entirely covered after implantation of CUF probe into a tumor mass. One end of the semipermeable hollow membrane fiber is glued with a small section of fused silica capillary (b) and attached to a PTFE tubing (c), while the other end is completely sealed with epoxy. A sharpened needle (e) is attached to the end of the PTFE ultramicrobore tube (d) and inserted into the vacutainer. Solid dots: tumor secretome.

Figure 2

The cRGD-induced apoptosis hypothetical pathway. The tripeptide RGD is a common domain in ECM ligands (such as fibronectin, fibrinogen, and vitronectin) for integrin binding. cRGD is a synthetic tripeptide with a similar structure with RGD in the integrin binding ligands. This is a proposed signaling pathway by which interaction of cRGD with integrin α5β3 in the plasma membrane leads to cancer cell apoptosis via caspase-9 activation.