The Role of Cancer Stem Cells and Mechanical Forces in Ovarian Cancer Metastasis

Abstract

Ovarian cancer is an extremely lethal gynecologic disease; with the high-grade serous subtype predominantly associated with poor survival rates. Lack of early diagnostic biomarkers and prevalence of post-treatment recurrence, present substantial challenges in treating ovarian cancers. These cancers are also characterized by a high degree of heterogeneity and protracted metastasis, further complicating treatment. Within the ovarian tumor microenvironment, cancer stem-like cells and mechanical stimuli are two underappreciated key elements that play a crucial role in facilitating these outcomes. In this review article, we highlight their roles in modulating ovarian cancer metastasis. Specifically, we outline the clinical relevance of cancer stem-like cells, and challenges associated with their identification and characterization and summarize the ways in which they modulate ovarian cancer metastasis. Further, we review the mechanical cues in the ovarian tumor microenvironment, including, tension, shear, compression and matrix stiffness, that influence (cancer stem-like cells and) metastasis in ovarian cancers. Lastly, we outline the challenges associated with probing these important modulators of ovarian cancer metastasis and provide suggestions for incorporating these cues in basic biology and translational research focused on metastasis. We conclude that future studies on ovarian cancer metastasis will benefit from the careful consideration of mechanical stimuli and cancer stem cells, ultimately allowing for the development of more effective therapies.

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

“…This value fell within the physiological ranges estimated for growth-induced (4.7 -18.9 kPa) and external (3.7 -16.0 kPa) compression [28]. The latter has been suggested to be a more noteworthy contributor to the total perceived stress [26] and estimated to exceed 20 kPa based on the experimental data from murine tumors [28]. Following this cycle, more cells were permanently damaged, appearing as dead after step '1j' at 370 mbar (contact pressure of 23.8 kPa from simulation in Fig.…”

“…When compared to cyclic loading, static compressive stimulation enhanced the aspect ratio of the OVCAR3 cells, but no di↵erence in cellular proliferation could be observed. This results is of particular interest, as chronic mechanical loading has been postulated to aid in ovarian cancer progression, forming a positive feedback loop [26]. Clearly, the e↵ects of cyclic compression require further study and applied cyclic pressures need to be expanded from the range of 3.9 to 6.5 kPa used by Novak et al [17] to the physiologically-relevant 3.7 to 18.9 kPa and above estimated to occur in human tumors [26,28].…”

“…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].…”

Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor

“…This fluid build-up submerges the ovaries in an aberrant mechanical microenvironment that further compresses the primary tumor site through hydrostatic pressure. As patients go about their everyday routine, the movement and placement of the ascites alters hydrostatic pressure in a time dependent manner [ 5 , 6 ]. This resulting compression stimulates the cells and impacts downstream signaling, known as mechanotransduction.…”

Suppression of Ovarian Cancer Cell Growth by AT-MSC Microvesicles

“…Cancer stem cells constitute a small population of tumor cells and play an important role in metastasis. Moreover, these cells are resistant to widely used drugs, which often leads to tumor recurrence [3]. Thus, a search for effective factors is needed that inhibit the biological activity of CSCs.…”