Tumor microenvironment: What can effusions teach us?

Abstract

Malignant effusions, which are composed of malignant pleural and peritoneal fluid, are an unusual manifestation of cancer and frequently portend a poor prognosis. Neoplastic cells that disseminate into cavities containing effusions are highly metastatic and possess a strong autonomous proliferative drive while concurrently being stimulatory of exudative effusions. Most effusions will respond to transient therapeutic intervention, including the obliteration of potential space via pleurodesis. Cure, however, is rare, thus making effusions a biologically, biochemically, and clinically important topic of study. The local microenvironment that supports malignant growth, invasion, and dissemination of the solid primary tumor into the vasculature is composed of activated stroma that includes scaffolding consisting of materials that promote the tumor function, and vascular structures to provide conduits for travel and nutrient delivery. Less is understood about the tumor-cell microenvironment in malignant effusions. The fluid nature of such a microenvironment when compared with the solid primary tumor may have significant implications for disease dissemination and progression. Dissecting the signaling activity and components of such microenvironments will improve our understanding and ultimately our ability to provide better patient care.

Normalization of the Ovarian Cancer Microenvironment by SPARC

“…Our previous findings that ascitic fluid from SP À/À mice enhanced the invasiveness and, to a lesser extent, the adhesion of ID8 cells (25) led us to investigate the possible mechanisms by which SPARC modulates the interplay of VEGF and MMPs in the milieu of the ascitic fluid. Consistent with our earlier report, the difference between SP +/+ and SP À/À ascitic fluid -induced adhesion was found to be insignificant but markedly inhibited by a VEGF neutralizing antibody, sFlt [2][3][4][5][6][7][8][9][10][11] , and a VEGFR2 (KDR) tyrosine kinase inhibitor, suggesting an autocrine effect of VEGF produced by ID8 cells themselves (Fig. 3A).…”

“…The proinvasive properties of malignant ascites have been shown to be mediated through the interplay of VEGF and MMPs (2,41,(45)(46)(47). Our previous findings that ascitic fluid from SP À/À mice enhanced the invasiveness and, to a lesser extent, the adhesion of ID8 cells (25) led us to investigate the possible mechanisms by which SPARC modulates the interplay of VEGF and MMPs in the milieu of the ascitic fluid.…”

“…C. Basal adhesion of ID8 cells to fibronectin was measured after pretreatment with SPARC (20 Ag/mL, 2 h), VEGF neutralizing antibody, Flt [2][3][4][5][6][7][8][9][10][11] , and KDR2 inhibitor IV as described above. D. Basal fibronectin invasion by ID8 cells after pretreatment with SPARC, VEGF neutralizing antibody, Flt [2][3][4][5][6][7][8][9][10][11] , and KDR2 inhibitor IV was done exactly as described in (A). ID8-VEGF cell adhesion to (E) and invasion of (F) fibronectin were tested as described above.…”

“…The ability of floating ovarian cancer cells in these malignant effusions to survive, proliferate, and disseminate in the absence of immediate proximity to a solid scaffold and vascular structures has been attributed to the unique, yet poorly defined, permissive microenvironment of these dense exudative fluids (1). The high autonomous proliferation rate of the metastatic ovarian cancer cells, their ability to develop alternative means of survival, as well as the contributions of inflammatory cells present in malignant effusions are believed to be responsible for the pluoripotent nature of these malignant effusions (2)(3)(4)(5). Ovarian cancer cells and peritoneal mesothelial cells constitutively produce bioactive lipids and cytokines that further promote motogenesis and mitogenesis of ovarian cancer cells in both autocrine and paracrine fashion (6)(7)(8)(9).…”

Incorporation of anti-angiogenesis therapy in the management of advanced ovarian carcinoma—Mechanistics, review of phase III randomized clinical trials, and regulatory implications

“…These processes are dependent on cytokines, extracellular matrix proteins, growth factors, proteolytic enzymes, and inflammatory cells [4,[6][7][8][9][10]. Ultimately, angiogenesis and tumor neovascularization herald cancer growth and dissemination.…”