The interstitial space in normal tissue and tumors. Top: The interstitium (i.e., loose connective tissue outside the blood and lymph vessels) in normal tissue consists of interstitial fluid and a solid extracellular matrix (ECM) again consisting of collagen fibers, glycosaminoglycans, i.e., hyaluronan and proteoglycans and fibroblasts. Notice the lymphatic vessel that is filled and drains filtered fluid and immune cells. Bottom: The interstitium in tumors is more disorganized than in normal tissue, and tumors have a so-called reactive stroma. A normal stroma in most organs contains a minimal number of fibroblasts, whereas reactive stroma is associated with an increased number of fibroblasts, enhanced capillary density and irregular blood vessels that have high microvascular permeability, again resulting in extravasation of plasma proteins such as fibrin, which in turn attract an influx of fibroblasts, inflammatory cells and endothelial cells. Compared with non-neoplastic tissue, the tumor stroma contains increased amounts of collagen having variable fiber size, proteoglycans and glycosaminoglycans, especially hyaluronan and chrondroitin sulfate. Tumors have lymphatics, at least in the periphery, but lymphatics may be compressed (pictured as a flattened lymph vessel) and thus nonfunctional.