Interstitial fluid-a reflection of the tumor cell microenvironment and secretome.

The interstitium or interstitial space describes the space outside the blood and lymphatic vessels. It contains two phases; the interstitial fluid (IF) and the extracellular matrix. In this review we focus on the interstitial fluid phase, which is the physical and biochemical microenvironment of the cells, and more specifically that of tumors. IF is created by transcapillary filtration and cleared by lymphatic vessels, and contains substances that are either produced and secreted locally, thus denoted secretome, or brought to the organ by the circulation. The structure of the interstitium is discussed briefly and moreover techniques for IF isolation focusing on those that are relevant for studies of the secretome. Accumulated data show that tumor IF is hypoxic and acidic compared with subcutaneous IF and plasma, and that there are gradients between IF and plasma giving information on where substances are produced and thereby reflecting the local microenvironment. We review recent data on the origin of tissue specific substances, challenges related to isolating a representative secretome and the use of this as a substrate for biomarker identification. Finally we perform a comparative analysis across human tumor types and techniques and show that there is great variation in the results obtained that may at least partially be due to the isolation method used. We conclude that when care is taken in isolation of substrate, analysis of the secretome may give valuable biological insight and result in identification of biomarker candidates. This article is part of a Special Issue entitled: An Updated Secretome.