Principles of dormancy evident in high-grade serous ovarian cancer

Abstract

In cancer, dormancy refers to a clinical state in which microscopic residual disease becomes non-proliferative and is largely refractory to chemotherapy. Dormancy was first described in breast cancer where disease can remain undetected for decades, ultimately leading to relapse and clinical presentation of the original malignancy. A long latency period can be explained by withdrawal from cell proliferation (cellular dormancy), or a balance between proliferation and cell death that retains low levels of residual disease (tumor mass dormancy). Research into cellular dormancy has revealed features that define this state. They include arrest of cell proliferation, altered cellular metabolism, and unique cell dependencies and interactions with the microenvironment. These characteristics can be shared by dormant cells derived from disparate primary disease sites, suggesting common features exist between them.High-grade serous ovarian cancer (HGSOC) disseminates to locations throughout the abdominal cavity by means of cellular aggregates called spheroids. These growth-arrested and therapy-resistant cells are a strong contributor to disease relapse. In this review, we discuss the similarities and differences between ovarian cancer cells in spheroids and dormant properties reported for other cancer disease sites. This reveals that elements of dormancy, such as cell cycle control mechanisms and changes to metabolism, may be similar across most forms of cellular dormancy. However, HGSOC-specific aspects of spheroid biology, including the extracellular matrix organization and microenvironment, are obligatorily disease site specific. Collectively, our critical review of current literature highlights places where HGSOC cell dormancy may offer a more tractable experimental approach to understand broad principles of cellular dormancy in cancer.

Keywords: Autophagy; Cellular quiescence; High-grade serous ovarian cancer; Metastasis; Minimal residual disease; Spheroid; Stress adaptation signaling; Tumor dormancy; Tumor microenvironment.

Fig. 1

Intraperitoneal dissemination of high-grade serous ovarian cancer. A Malignant cells are shed from the primary tumor into the peritoneal space. This often occurs within the accumulated ascites fluid in advanced stage HGSOC. The ability of metastatic HGSOC cells to exist as multicellular clusters, called spheroids, affords malignant cells with enhanced survival characteristics. The induction of a dormancy phenotype thereby protects them from chemotherapeutic insult. Spheroids have an enhanced capacity to reattach to the mesothelial surfaces of the peritoneal cavity to seed secondary tumor deposits and re-initiate cell growth and invasion. B, C Phase contrast microscopic images of spheroids filtered from HGSOC patient-derived ascites fluid (B) and spheroids generated by in vitro suspension culture (C). D Image of secondary tumor deposits visible on the peritoneal wall of an HGSOC patient undergoing laparoscopic surgery. Photo in (D) courtesy of Dr. Dominique Lanvin

Fig. 2

Mechanisms controlling cellular dormancy in HGSOC spheroids. A HGSOC spheroid cells undergo several stress induced reprogramming events to induce cellular quiescence through p38 and ERK regulation. These lead to increased expression of CDK inhibitors, assembly of DREAM, and inhibition of CDK activity. Additional pathways contribute to the dormancy phenotype, including metabolic reprogramming via increased LKB1 and AMPK activities, decreased PI3K-AKT signaling, and the induction of macroautophagy. EMT and stemness are promoted by TGFβ and WNT signaling, respectively, and these ligands can be produced directly by HGSOC cells or by other cells within the microenvironmental niche. B HGSOC spheroids may be directly impacted by numerous different cell types of the unique microenvironment of the peritoneal cavity and malignant ascites fluid. These include tumor-associated macrophages, fibroblasts, and T-cells, all of which can provide cytokine signals or direct cell-cell contacts to impact the dormant phenotype. Spheroids directly interact with mesothelial cells on peritoneal surfaces, leading to mesothelial clearance and invasion into the underlying stroma. During this process, HGSOC cells can undergo a dormant-to-proliferative switch, as well as reverse their mesenchymal phenotype when establishing secondary tumor deposits