ReviewMulticellular spheroids in ovarian cancer metastases: Biology and pathology
Introduction
Ovarian cancer is the leading cause of gynecological cancer mortality world wide [1], however, it is a relatively rare disease with approximately 1450 to 1500 Australian women and 23,000 American women diagnosed each year (an age-standardized rate of ∼ 12.6 new cases per 100,000 head population in Australia and ∼ 15.4 in the USA) [2]. Unfortunately though, when compared to other cancers, the mortality rate for ovarian cancer is high, resulting in more than 850 deaths per annum in Australia and 15,000 in the USA. A significant contributor to the high mortality rate is that, despite good initial responses to chemotherapy, recurrence is common and often fatal. It is, therefore, imperative that research into ovarian cancer focuses on better treatments for intermediate and late stage disease in addition to identifying markers of disease progression.
Characteristically, initial EOC dissemination is intra-abdominal involving local invasion of pelvic and abdominal organs but rarely involving the vasculature [3]. Our working hypothesis is that malignant cells are shed from the primary tumor into the peritoneal cavity where they are disseminated throughout the abdominal cavity by peritoneal fluid or ascites. These malignant cells often aggregate and form spheroid-like structures [3], [4] and we propose that these aggregates could attach to and invade the peritoneum and potentially seed metastatic tumor growth. Additionally, spheroids that are present in malignant ascites may represent a significant impediment to efficacious treatment of late stage EOC where the anchorage-/vascular-independent growth restrictions as well as the creation of a nutrient density gradient may restrict the ability of therapies to completely clear the disease. Currently, there is data to demonstrate that spheroids are commonly found in ascites, are capable of tumorgenesis in vivo, and have a reduced response to chemotherapeutic drugs in vitro[5], [6], [7], [8]. The purpose of this review is to highlight the role of spheroids in EOC dissemination and chemo-responses as well as to provide insights into spheroid functionality and to identify key areas of deficiency with current methods.
Section snippets
Origins and progression of ovarian cancer
The specific cellular origin of ovarian cancer remains contentious. While it is generally accepted that there are three main cellular origins of ovarian cancer, the epithelium (∼ 90%), germ cells (∼ 5%) and stromal cells (∼ 5%) (OvCa Patient information, 2007, http://www.ovca.org.au), the specific role of the ovarian surface epithelium (OSE) as the source of all epithelial ovarian cancer (EOC) remains equivocal [9], [10]. An unusual characteristic of ovarian cancer is that early in progression the
A model of ovarian cancer metastasis
A current model for EOC metastasis is illustrated in Fig. 1 (adapted from [19]). Briefly, the development of peritoneal metastases in EOC is regulated, to a large extent, by the ability of shed ovarian tumor cells to survive and subsequently attach to and infiltrate the mesothelial lining of the abdominal cavity. Cells shed from the primary tumor aggregate as spheroids within the abdominal cavity then settle onto the surface of the peritoneum where disaggregation and metastatic outgrowth may
Mechanisms of spheroid formation
It is proposed that cells shed from the primary tumor aggregate as spheroids within the abdominal cavity in order to maintain cell–cell contact and co-stimulation under anchorage-independent growth conditions. It, therefore, follows that when normally adherent cells are forced into suspension, the cells will spontaneously aggregate in a manner consistent with a normal/natural survival response. Subsequent compaction then requires separate, but complementary mechanism(s) to strengthen the
Spheroids and chemoresistance
Spheroids can be generated by culturing adherent ovarian cancer cells under conditions where attachment to matrices is prevented [40]. This type of cellular manipulation has been used in the past primarily to investigate the mechanism(s) of drug resistance in three-dimensional solid tumors [6], [41], [42], [43], [44]. As a peritoneal model of metastasis, the formation of an unvascularized 3-D spheroid has the potential to generate a structure with a metabolite density gradient that can inhibit
Implications of spheroids on EOC treatment outcomes
Cytoreductive surgery and chemotherapy are the primary components of standard first line treatment for ovarian cancer. In order to negate the need for any additional surgical procedures, ‘optimal’ primary cytoreduction (residual tumor ≤ 1 cm) and surgical staging are performed in parallel and complete ‘optimal’ cytoreduction is attempted whenever possible since there is an inversely proportional association between improved survival outcomes and a residual tumor burden of less than 1 cm (in any
Future directions for spheroid research
The most pertinent future aim will be to establish and validate in vitro based assays using various ex situ and/or in vivo functional analyses. There are a couple key research areas that address this issue and should be further explored. Burleson et al. [23] identified a small population of ex situ spheroids (isolated from malignant ascites) that could adhere to and disaggregate on matrices in an in vitro assay. This approach allows limited functional analysis of in vivo spheroids that could
Summary
Available data support the role of spheroids in EOC disease progression. Spheroids are commonly found in the ascites, have been shown to have adherent and migratory ability and are able to establish metastatic lesions upon intraperitoneal injection of SCID mice. Currently, the majority of chemotherapies are ineffective in preventing spheroid growth and dissemination. In particular, they do not inhibit anchorage- and vascular-independent growth associated with a 3-dimensional structure. As such,
Conflict of interest statement
The authors have no conflicts of interest to declare.
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