Ascites-induced compression alters the peritoneal microenvironment and promotes metastatic success in ovarian cancer

Abstract

The majority of women with recurrent ovarian cancer (OvCa) develop malignant ascites with volumes that can reach > 2 L. The resulting elevation in intraperitoneal pressure (IPP), from normal values of 5 mmHg to as high as 22 mmHg, causes striking changes in the loading environment in the peritoneal cavity. The effect of ascites-induced changes in IPP on OvCa progression is largely unknown. Herein we model the functional consequences of ascites-induced compression on ovarian tumor cells and components of the peritoneal microenvironment using a panel of in vitro, ex vivo and in vivo assays. Results show that OvCa cell adhesion to the peritoneum was increased under compression. Moreover, compressive loads stimulated remodeling of peritoneal mesothelial cell surface ultrastructure via induction of tunneling nanotubes (TNT). TNT-mediated interaction between peritoneal mesothelial cells and OvCa cells was enhanced under compression and was accompanied by transport of mitochondria from mesothelial cells to OvCa cells. Additionally, peritoneal collagen fibers adopted a more linear anisotropic alignment under compression, a collagen signature commonly correlated with enhanced invasion in solid tumors. Collectively, these findings elucidate a new role for ascites-induced compression in promoting metastatic OvCa progression.

MAPK Signaling Is Required for Generation of Tunneling Nanotube-Like Structures in Ovarian Cancer Cells

“…In agreement with studies by Dr. Stack, TnTs were not found in mesothelial-tumor cell co-cultures in the absence of external pressure. In their studies, it was found that compression increased TnT formation between peritoneal cells and tumor cells [ 29 ]. Ongoing studies suggest that mesothelial/OCC induce production of FGFs and EGF growth factors in mesothelial cells that may create a paracrine loop that enables tumor cell growth and invasion.…”

A flexible micro-piston device for mechanical cell stimulation and compression in microfluidic settings

“…As a result, the application of mechanical compression on living cells, such as cancerous [5,[9][10][11][12][13][14][15][16][17][18][19], non-cancerous and stromal cells [20][21][22], neurons [23] and chondrocytes [24], has gained importance in recent years. Compression applied on cancer types, such as breast [5,16,18,19], brain [13], pancreatic [9] and ovarian [17,25] cancer cells, resulted in more invasive and metastatic forms. While indicative, previous studies all point out the need for further investigations to understand the e↵ect of compressive mechanical stimuli in metastasis of di↵erent cancer types, for example ovarian cancer [17,25,26].…”

“…Asem et al [25] and Klymenko et al [27] applied static compression at ⇠3 kPa and at 3.18-3.53 kPa, respectively, on ovarian cancer models in o↵-chip settings. On the other hand, a recent work by Novak et al remains the only study to date using a bioreactor device, which is yet at millimeter scale, to investigate the e↵ect of compressive mechanical stress on ovarian cancer [17].…”

“…Compression applied on cancer types, such as breast [5, 16, 18, 19], brain [13], pancreatic [9] and ovarian [17, 25] cancer cells, resulted in more invasive and metastatic forms. While indicative, previous studies all point out the need for further investigations to understand the effect of compressive mechanical stimuli in metastasis of different cancer types, for example ovarian cancer [17, 25, 26]. Ovarian cancer cells are exposed to compressive stress mainly by tumor growth, native tissue and hydrostatic pressure from the ascites [25, 26].…”

“…While indicative, previous studies all point out the need for further investigations to understand the effect of compressive mechanical stimuli in metastasis of different cancer types, for example ovarian cancer [17, 25, 26]. Ovarian cancer cells are exposed to compressive stress mainly by tumor growth, native tissue and hydrostatic pressure from the ascites [25, 26]. SKOV-3 is among the ovarian cancer cell lines tested to be responsive to compressive stimuli and has metastatic phenotype.…”