1/6/2024 0 Comments Interstitial fluidIn a more extensive recent review, we have summarized literature on the formation of IF and TIF ( 7) and in another we have focused on the tumor secretome ( 8). Although of interest in itself, fluids that are biologically more proximal to the disease site and thereby called proximal fluids (e.g., TIF) are also important elements in a more integrated approach toward biomarkers, also involving, e.g., tumor tissue, serum, and cancer cell lines ( 6). In the last part of the review, we will outline potential biological and clinical implications of new knowledge regarding secreted proteins and tissue microenvironment in tumors with respect to local signaling and the possible translation into new biomarkers. Our aim is to summarize recent studies on TIF where the focus has been locally secreted substances that will appear in the tumor at high concentrations, eventually appearing in the blood and thus reflecting processes at the tissue level. Here, we will review in brief the structure of the tumor ECM as a part of a general description of the tumor interstitium before we turn to the formation of TIF and techniques for fluid isolation of most relevance for the secretome, i.e., substances secreted by the tumor to the TIF. While tumor microenvironment studies have mostly been on the stroma and the cellular elements of the tumor, we will focus on the fluid phase that has received less attention ( 3– 5). The microenvironment consists of the insoluble elements of the ECM, the interstitial space with its non-tumor cellular elements (frequently referred to as stroma), and the fluid phase containing dissolved substances. Whereas in previous years, the focus has been on the tumor cell per se, during recent years, there has been an increasing interest in the tumor microenvironment shown to be of significant importance for tumor growth and metastasis. All of these are good reasons for including cells in the term “interstitium” here, notably those that are not organ specific, e.g., fibroblasts or immune cells, but rather an integrated part of the ECM. Cells in the interstitium, however, are active in continuous bi-directional cell–matrix interactions that result in microenvironmental changes, secrete substances to the IF and have important roles in initiating immune responses ( 2), and are a central element of the tumor interstitium. The tumor interstitial fluid (TIF) is not only a transport medium for nutrients and waste products between cells and capillary blood, but also contains an abundance of substances that are either produced locally or transported to the organ by the blood circulation.Ĭells have traditionally not been included in this concept of the interstitium ( 1). This space is located outside the blood and lymph vessels and parenchymal cells, and consists of two major phases: the interstitial fluid (IF) and the structural molecules comprising the extracellular matrix (ECM). The interstitium, or interstitial space, is a general term applied for connective and supporting tissues in the body. Access to TIF that reliably reflects the local tumor microenvironment enables identification of substances that can be used in early detection and monitoring of disease. Potential biomarkers will appear locally in high concentrations in tumors and may eventually be found diluted in the plasma. The development of sensitive proteomic technologies has made TIF a valuable source for tumor specific proteins and biomarker candidates. There appear to be local gradients in signaling substances from neoplastic tissue to plasma that may provide new understanding of tumor biology. TIF is formed by transcapillary filtration, and since this fluid is not readily available we discuss available techniques for TIF isolation, results from subsequent characterization and implications of recent findings with respect to fluid filtration and uptake of macromolecular therapeutic agents. Access to this space may provide important insight into tumor development and therapy response. This is a component of the internal milieu of a solid tumor that has attracted regained attention. In the present review, we focus on the interstitial fluid phase of solid tumors, the tumor interstitial fluid (TIF), i.e., the fluid bathing the tumor and stroma cells, also including immune cells. The interstitium, situated between the blood and lymph vessels and the cells, consists of a solid or matrix phase and a fluid phase representing the tissue microenvironment. Department of Biomedicine, University of Bergen, Bergen, Norway.
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