LACK OF FUNCTIONING LYMPHATICS AND ACCUMULATION OF TISSUE FLUID/LYMPH IN INTERSTITIAL “LAKES” IN COLON CANCER TISSUE

Abstract

There is controversy as to whetherintratumoral or peritumoral lymphatics playa dominant role in the metastatic process.The knowledge of how and where exactlytumor cells enter lymphatics is important fortherapeutic targeting either the tumor core orperitumoral tissue with drugs or radiation.The basic questions remain: what is themorphological structure of intra- andperitumoral interstitium and lymphatics; whatis their hydraulic conductivity?; and do theselocal physical conditions allow detached tumorcells to migrate to lymphatics? Identificationof lymphatics has been based on immunohistochemicalstaining of lymphatic endothelialcells. This method does not, however, showthe tissue fluid filled interstitial space and theshape of minute lymphatic vessels in tumors.We visualized the interstitial space andlymphatics in the central and peripheralregions of tumors using our original methodof color stereoscopic lymphography in translucenttissue fragments and simultaneouslywith immunohistochemical staining oflymphatic and blood endothelial cells. Thedensity of open and compressed lymphatic andblood vessels was measured in the intratumoral“hot spots” and at tumor edge. Moreover,the intratumoral tissue hydraulic conductivitywas measured to define force necessary forpropelling tissue fluid to peritumorallymphatics. We found very few rudimentaryminor blind lymphatics in the tumor core andnumerous minor fluid “lakes”in theinterstitium with no visible connection to theperitumoral lymphatics. Lining of “lakes” didnot express molecular markers specific forlymphatic endothelial cells. Ninety-fivepercent of structures of what looked likelymphatics had compressed lumen and thehydraulic conductivity was 3 powers ofmagnitude lower than in the adjacent nontumoraltissue. It can be concluded that lackof functioning lymphatics in tumor focimanifested by accumulation of tissue fluid in“lakes,” low fluid conductivity and compressionof lymphatics by tumor cells, and proliferatingconnective tissue may hamper escape of tumorcells. The most favorable site of entry oftumor cells to lymphatics seems to be theinterface of the tumor and surrounding tissuewith open lymphatics.