The Role of Intra-Tumoral Heterogeneity and Its Clinical Relevance in Epithelial Ovarian Cancer Recurrence and Metastasis

Abstract

Epithelial ovarian cancer is the deadliest gynecologic cancer, due in large part to recurrent tumors. Recurrences tend to have metastasized, mainly in the peritoneal cavity and developed resistance to the first line chemotherapy. Key to the progression and ultimate lethality of ovarian cancer is the existence of extensive intra-tumoral heterogeneity (ITH). In this review, we describe the genetic and epigenetic changes that have been reported to give rise to different cell populations in ovarian cancer. We also describe at length the contributions made to heterogeneity by both linear and parallel models of clonal evolution and the existence of cancer stem cells. We dissect the key biological signals from the tumor microenvironment, both directly from other cell types in the vicinity and soluble or circulating factors. Finally, we discuss the impact of tumor heterogeneity on the choice of therapeutic approaches in the clinic. Variability in ovarian tumors remains a major barrier to effective therapy, but by leveraging future research into tumor heterogeneity, we may be able to overcome this barrier and provide more effective, personalized therapy to patients.

Ovarian Cancer, Cancer Stem Cells and Current Treatment Strategies: A Potential Role of Magmas in the Current Treatment Methods

“…In addition to different origins of HGSOC, OC progression is further made complex by tumour heterogeneity, which can be classified as either inter-tumour, or intra-tumour heterogeneity [7]. Inter-tumour heterogeneity occurs if the genotypic and phenotypic variation exists between multiple tumour cells from one patient, for example the primary lesion of OC patients may be different in genotype and phenotype from the tumours of distant omental metastasis [34].…”

“…Inter-tumour heterogeneity occurs if the genotypic and phenotypic variation exists between multiple tumour cells from one patient, for example the primary lesion of OC patients may be different in genotype and phenotype from the tumours of distant omental metastasis [34]. On the other hand, intra-tumour heterogeneity occurs if genotypic and phenotypic variation occurs within the same tumour of primary lesion or distant metastases [7,35]. Both inter-and intra-tumour heterogeneity occurs in OC as well as in most cancers and is the primary cause of disease progression and importantly therapeutic resistance and relapse [7].…”

“…On the other hand, intra-tumour heterogeneity occurs if genotypic and phenotypic variation occurs within the same tumour of primary lesion or distant metastases [7,35]. Both inter-and intra-tumour heterogeneity occurs in OC as well as in most cancers and is the primary cause of disease progression and importantly therapeutic resistance and relapse [7]. Tumour heterogeneity in OC can arise from genetic or epigenetic changes as well as clonal expansion of cells driven by these changes [7].…”

“…Both inter-and intra-tumour heterogeneity occurs in OC as well as in most cancers and is the primary cause of disease progression and importantly therapeutic resistance and relapse [7]. Tumour heterogeneity in OC can arise from genetic or epigenetic changes as well as clonal expansion of cells driven by these changes [7].…”

“…Recurrent OC remains a major challenge since there is >80% patient mortality within 5 years [6]. The failure of chemotherapy treatment in OC is a likely result of tumour heterogeneity, lack of targetable effects on tumour microenvironment, and the likely presence of pre-existing or acquired chemoresistant cancer cells or cancer stem cells (CSCs) [7,8].…”