Tumor interstitial fluid as modulator of cancer inflammation, thrombosis, immunity and angiogenesis

Tumor interstitial fluid (TIF) is a watery phase that accumulates inside the tumor interstitium. Its genesis and fate depend on various factors, namely tumor type, metabolic state of the tumor, expression of vascular endothelial growth factor, and absence of lymphatic system. For almost 30 years TIF remained a neglected entity until it was demonstrated that TIF, and in particular its high pressure, constitutes an important obstacle to drug delivery and immunotherapy. The present review not only summarizes the abundant literature on the processes of TIF genesis and on its effects on therapy but it also presents data that, in our opinion, point towards what is perhaps the real physiological purpose of TIF: a primitive means of providing nourishment, oxygen, cytokines and matrikines to tumor cells that furthermore promotes the invasion of the normal surrounding tissue and passive metastatization through lymphatics. It is also an inducer of inflammation through increased osmolarity due to albumin loss. Recently, a role for TIF as a possible source of biomarkers has also been suggested.