**2. Overview of ovarian cancer metastasis**

The lack of an anatomic barrier allows the ovarian cancer cells to very conveniently spread into the peritoneal cavity. The cancer cells on the surface of the primary tumors start loosing cell–cell contact and become loosely attached to each other. As a result of this, they become prone to exfoliation into the peritoneal cavity (**Figure 1**). Exfoliation is promoted by the mechanical forces like rubbing of neighboring peritoneal organs during respiratory move‐ ments and flow of the peritoneal fluids. The cancer cells may come off as single cells or as clumps. This is a passive mode of dissemination unlike the typical invasion followed by intravasation observed in tumors undergoing hematogenous metastasis [13, 17, 18]. The peritoneal fluid naturally flows within the peritoneal cavity upward, toward the head, and then back downward, toward the feet, as a result of the diaphragm movement during respiration and gravitational pull, respectively [19]. The exfoliated ovarian cancer cells from the primary tumor are disseminated throughout the peritoneal cavity by this natural flow of the peritoneal fluid (**Figure 1**). Since normally there is only a small volume of the peritoneal fluid present, dissemination is predominantly limited to the organs in the vicinity of the primary tumor [17]. As the disease progresses, more and more ascites is produced and this enables the spread of the cancer cells to more distant sites in the abdomen. One of the pre‐ dominant sites of ovarian cancer metastasis is the omentum which is a fatty double fold of the peritoneal membrane, about 8 by 8 inches in size, covering the bowels [13]. It is important to note that this mode of spreading typical of ovarian cancer is very different in terms of the hydrodynamic forces experienced by the cancer cells when they are carried rapidly in the blood vessels during hematogenous metastasis [20, 21].

Epithelial cells tend to undergo anoikis in the absence of attachment to a substratum. Therefore, the main challenge faced by the cancer cells floating in the peritoneal fluid is overcoming anoikis and surviving floatation. In addition, they have to avoid immune surveillance. The cancer cells either form aggregates or spheroids or exist as single cells (**Figure 1**) [22]. The spheroids may also contain embedded cancer‐associated fibroblasts as well as activated mesothelial cells, which contribute to the development of the ascetic microenvironment [22]. The subsequent challenge for these floating cancer cells is to successfully attach to the surface of the organs in the peritoneal cavity (**Figure 1**). Debulking surgery often reveals such spheroids loosely attached to the peritoneum. The mesothelial cells covering the peritoneum and the bowels secrete mucus like substances, which help in reducing friction between surfaces as they brush against each other during the course of the organs' natural movements. The same also helps in preventing attachment of the cancer cells to some extent. However, the integrins expressed by the metastasizing cells help them to attach to the extra cellular matrix proteins (ECMs) secreted by the mesothelial cells. Thereafter, the cancer cells are able to push apart the mesothelial cells forming the protective barrier and invade into the organ [23, 24].

Having invaded through the mesothelium of the site of metastasis, the cancer cells have to now revert back to their normal self of growing attached to a substratum. However, since they are now encountering a new microenvironment with a potentially different ECM and secreted factors, they have to now adapt to these new conditions. The adaptive process involves extensive and productive reciprocal interactions between the cancer cells and the normal microenvironment of the metastatic site [6]. Those cells, which are able to successfully adapt to this new microenvironment, go on to eventually establish metastatic colonies. On the other hand, the cells that cannot productively interact and adjust to the new microenvironment eventually perish or remain dormant. The cells that are successful eventually reprogram the microenvironment to form and 'activated tumor stroma,' which include cancer‐associated fibroblasts, endothelial cells, immune cells, and modified ECMs that promote tumor growth at the metastatic site. In addition to the peritoneal dissemination described above, ovarian cancer cells have been found in blood circulation and recent reports have indicated the existence of an alternative hematogenous mode of metastasis [16, 25].

The process of attaching to and developing metastatic tumors in the new organ is known as metastatic colonization (**Figure 1**). It is considered the least efficient step in the whole process of metastasis [21, 26]. This is also evidenced in mouse xenograft experiments to study ovarian cancer metastasis where many millions of cancer cells are injected intraperitoneally and result in about a hundred tumors or even less [6, 27, 28]. At the same time, the mechanism of regulation of this step and the initial cross talk between the cancer cells and the microenvir‐ onment remains a mystery for the obvious difficulty in getting access to this window. Greater understanding of the biology of this process will enable the identification of key regulators that can be targeted therapeutically to hit the metastatic disease at its most vulnerable phase.
