Ovarian Cancer Spheroids Use Myosin-Generated Force to Clear the Mesothelium

Department of Cell Biology, Harvard Medical School, Boston, 02115 MA, USA.
Cancer Discovery (Impact Factor: 19.45). 07/2011; 1(2):144-57. DOI: 10.1158/2159-8274.CD-11-0010
Source: PubMed


Dissemination of ovarian tumors involves the implantation of cancer spheroids into the mesothelial monolayer on the walls of peritoneal and pleural cavity organs. Biopsies of tumors attached to peritoneal organs show that mesothelial cells are not present under tumor masses. We have developed a live, image-based in vitro model in which interactions between tumor spheroids and mesothelial cells can be monitored in real time to provide spatial and temporal understanding of mesothelial clearance. Here we provide evidence that ovarian cancer spheroids utilize integrin- and talin- dependent activation of myosin and traction force to promote mesothelial cells displacement from underneath a tumor cell spheroid. These results suggest that ovarian tumor cell clusters gain access to the sub-mesothelial environment by exerting force on the mesothelial cells lining target organs, driving migration and clearance of the mesothelial cells.

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Available from: Taru Muranen
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    • "The mechanism of intercalation seen in the clearance of mesothelial cells by ovarian cancer cell clusters could also be at play in addition to entosis, both requiring ROCK activity (Iwanicki et al., 2011). "
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    • "Intriguingly, the histopathological examination of the excised tumors (Fig. 4) revealed that in the case of xenografts generated upon injection of A2780, OVCAR- 3, and SKOV-3 cells, peritoneal mesothelial cells (identified according to the presence of the Wt1 antigen) were still present under the tumor mass, questioning to some extent the paradigm by Iwanicki et al. about the lack of mesothelium under cancerous tissue [3]. The presence of mesothelial cells, staying in agreement with the results of Steinkamp et al. [23], may imply that their involvement in peritoneal ovarian cancer metastasis not only encompasses the very early steps of cancer cell dissemination (until their " clearance " [3] [15]), but may also last continuously, probably amplifying their harmful Fig. 4. Microscopic evaluation of tumors excised from the mouse peritoneal cavity after i.p. injection of ovarian cancer cells. Results of the tumor examination using h+e staining (left panel). "
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    ABSTRACT: The role of mesothelial cells in the intraperitoneal spread of ovarian cancer is still elusive. In particular, it is unclear whether these cells constitute a passive barrier preventing cancer cell progression or perhaps act as an active promoter of this process. In this report we show that omental human peritoneal mesothelial cells (HPMCs) stimulate adhesion and proliferation of ovarian cancer cells (A2780, OVCAR-3, SKOV-3). The latter was associated with the paracrine activity of GRO-1, IL-6, and IL-8 released to the environment by HPMCs. Furthermore, the growth dynamics of ovarian cancer xenografts produced in response to i.p. injection of ovarian cancer cells together with HPMCs was remarkably greater than for implantation of cancer cells alone. A layer of peritoneal mesothelium was consistently present in close proximity to the tumor mass in every xenograft model. In conclusion, our results indicate that HPMCs play a supporting role in the intraperitoneal invasiveness of ovarian malignancy, whose effect may be attributed to their ability to stimulate adhesion and proliferation of cancer cells.
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    • "There are three proposed methods of cancer cell migration through the endothelium: (a) cancer cells may migrate through the EC body [10], (b) cancer cells may induce EC apoptosis [10], [13] and (c) cancer cells may migrate through endothelial cell-cell junctions without permanently destroying the EC layer [11]. In recent years, research has also shown that cancer cells also exert forces on ECs that push them deeper into the extracellular matrix during transmigration [15], [16], and that the endothelium enhances cancer cell migration [17]. These findings suggest that cancer migration through the endothelium is a complex process that requires further investigation to elucidate its mechanistic course. "
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