ReviewTargeting the tumour microenvironment in ovarian cancer
Introduction
The study of cancer initiation, growth, and metastasis has traditionally been focused on cancer cells. This view postulates that cancer cells proliferate due to uncontrolled growth signalling pathways owing to derangements in both oncogenes and tumour suppressor genes [1]. However, despite the significant contributions of these pathways in the metastatic transformation of cells, the uncontrolled growth that occurs in tumours cannot be explained solely by aberrations in the cancer cells themselves. Tumours are complex tissues composed of tumour cells, as well as stroma consisting of blood and lymphoid vessels, nerves, fibroblasts and extracellular matrix proteins, endothelial cells, pericytes, and immune cells [1]. These collectively comprise the tumour microenvironment. To fully understand the biological behaviour of tumours, it is essential to consider the context in which cancer cells exist, and how they manipulate and are manipulated by the surrounding stroma to promote the malignant phenotype [2].
Ovarian cancer is the second most common gynaecologic malignancy but is the most common cause of death from gynaecologic cancer worldwide [3], [4]. Epidemiology, treatment and prognosis vary greatly by histopathologic subtype. Epithelial ovarian carcinoma comprises approximately 85 percent of ovarian malignancies [5], [6], with high-grade serous (HGSC) being the most common histology.
While HGSC was historically thought to arise from the ovarian surface epithelium, contemporary paradigms suggest that other sources are more likely. Studies examining the distal, fimbriated end of the fallopian tubes in patients with serous carcinoma classified as either ovarian, fallopian tube or primary peritoneal in origin demonstrated that approximately 50% of patients had tubal intraepithelial carcinoma (TIC) present [7]. This suggests that TIC may be the precursor lesion and an important initiating factor in pelvic serous carcinoma [8]. Cells in the hilum of the ovary may be an alternative source of stem cells [9] and may have increased susceptibility to malignant transformation [9]. The primary mode of spread of HGSC was traditionally thought to be continuous exposure of the peritoneal surfaces to exfoliated tumour cells, however, there is evidence pointing to haematogenous mode of spread being an important component of the metastatic process [10], [11]. Ovarian cancer cells have tropism for the omentum, which is likely mediated by a variety of factors produced by omental adipocytes [12].
Herein, we review the key components of the tumour microenvironment as they pertain to ovarian cancer, discuss targeting opportunities for individual stromal cell types as well as their prognostic potential, and outline emerging areas of research. Emphasis will be placed on fibroblasts, endothelial cells, and the immune components of the tumour microenvironment.
Section snippets
Background
Fibroblasts are the principal cellular component of connective tissue and are largely responsible for its maintenance and regeneration. The functions of fibroblasts include production and deposition of types I, III and V collagen and fibronectin, which are key components the fibrillar extracellular matrix [13], as well as synthesis of basement membrane proteins laminin and type IV collagen [14]. In addition, fibroblasts have an important role in the turnover and maintenance of the extracellular
Background
The formation of new blood vessels is essential for tumour growth and metastasis [45]. Angiogenesis is a central hallmark of cancer and is crucial for solid tumour growth and metastasis [1]. Early studies demonstrated that tumour growth in isolated perfused organs was significantly decreased in the absence of tumour vascularisation [46], [47], and that without adequate vascularisation, tumour cells undergo necrosis or apoptosis [48], [49]. An ‘angiogenic switch’ becomes activated during the
Background
Immune cells are present not only in the tumour microenvironment, where they interact closely with fibroblasts and endothelial cells, but also in areas of the tumour predominated by cancer cells [87]. The importance of the interaction between cancer cells and immune cells was first described in 1863 by Virchow, who observed that cell proliferation was enhanced at sites of tissue injury and resultant inflammation [88], [89]. This concept is demonstrated by the fact that approximately 15% of
Conclusions
The treatment of epithelial ovarian cancer, particularly in the setting of platinum-resistant or -refractory disease, remains a challenge. Theoretically, targeting the tumour microenvironment is advantageous because stromal components do not develop mutations or genetic aberrations as frequently as do tumour cells. However, the intricate signals between components of the tumour microenvironment can ultimately lead to adaptive resistance and treatment failure. Many of the strategies outlined in
Conflict of interest statement
JMH and AKS report no conflicts of interest. RLC has clinical trial research grants from the National Cancer Institute, Abbvie, Clovis Oncology, AstraZeneca, Medimmune, Novartis, Oncomed, EMD-Serono, Array, Millennium, and Roche/Genentech.
Role of funding source
JMH is supported by a NIH T32 Training Grant CA101642. This work was also supported in part by NIH grants (P50CA083639, CA109298, P50CA098258, U54CA151668, UH2TR000943, CA177909, CA016672, U54CA96300 and U54CA96297), CPRIT RP 110595, an Ovarian Cancer Research Fund Program Project Development Grant, Department of Defense Grants (OC120547 and OC093416), The Betty Ann Asche Murray Distinguished Professorship, the RGK Foundation, the Gilder Foundation and the Blanton-Davis Ovarian Cancer Research
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