Tumor stroma derived biomarkers in cancer

Abstract

In recent years the importance of the tumor stroma for the development, promotion and invasion of cancer is becoming increasingly clear. Besides a malignantly transformed cancer cell, tumors also contains many other cell types, including endothelial cells, fibroblasts and cells of the immune system. These cells together with the cancer cells produce the sum extracellular matrix (ECM) of the tumor. The ECM and the non-malignant cells of the tumor are defined as the "tumor stroma". Just as the malignant cell itself can be the source of substances that can be used as biomarkers of cancer, the tumor stroma contains factors that potentially can be used as biomarkers when treating patients with cancer. In this review we will discuss the role of the tumor stroma as a source of new cancer biomarkers. This concept highlights a novel view of cancer and treats them as organized organs. Additionally, this further stresses the importance of including factors related to the tumor stroma into the diagnostic and therapeutic equation of cancer.

Figure 1

The tumor stroma. Cancer is much more than just a group of malignant cells and should be viewed more as an organ containing many different stromal cells such as fibroblasts, immune cells and the cells of the vasculature. Both stromal and cancer cells produce proteases that continuously remodel the ECM of the tumor. The ECM remodeling leads to release of substances sequestered in the ECM, as well as bio-active cleavage fragments from ECM proteins such as collagens.

Figure 2

A model for a stroma derived tumor biomarker and their potential utility. During tumor remodeling process, the stroma may release substances into circulation and they could potentially serve as a novel class of tumor biomarkers. Circulating levels would decrease with successful removal/treatment of the tumor and increase again when disease relapses. Additionally the expression pattern of a stromal biomarker in the primary tumor or metastasis can be of importance in predicting disease progression and outcome of the therapy.

Figure 3

Expression pattern of type XVIII collagen/endostatin in human breast cancer. a In normal breast tissue the type XVIII collagen/endostatin signal (in red) is located in the BM underlining the ductal epithelium as well as the BM of blood vessels. b In cancer the BM signal is lost from the epithelium and diffuse signal is now seen in the tumor stroma and co-localizing with the endothelial marker CD31 (in green) in the tumor vessels. Cell nuclei are stained with DAPI (in blue).