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Murine Model for Non-invasive Imaging to Detect and Monitor Ovarian Cancer Recurrence
Published on: November 2, 2014
Norepinephrine induces anoikis resistance in high-grade serous ovarian cancer precursor cells
Hunter D Reavis1,2,3, Stefan M Gysler1, Grace B McKenney1
1Penn Ovarian Cancer Research Center, Department of Obstetrics and Gynecology.
Abstract:
High-grade serous carcinoma (HGSC) is the most lethal gynecological malignancy in the United States. Late diagnosis and the emergence of chemoresistance have prompted studies into how the tumor microenvironment, and more recently tumor innervation, may be leveraged for HGSC prevention and interception. In addition to stess-induced sources, concentrations of the sympathetic neurotransmitter norepinephrine (NE) in the ovary increase during ovulation and after menopause. Importantly, NE exacerbates advanced HGSC progression. However, little is known about the role of NE in early disease pathogenesis. Here, we investigated the role of NE in instigating anchorage independence and micrometastasis of preneoplastic lesions from the fallopian tube epithelium (FTE) to the ovary, an essential step in HGSC onset. We found that in the presence of NE, FTE cell lines were able to survive in ultra-low-attachment (ULA) culture in a β-adrenergic receptor-dependent (β-AR-dependent) manner. Importantly, spheroid formation and cell viability conferred by treatment with physiological sources of NE were abrogated using the β-AR blocker propranolol. We have also identified that NE-mediated anoikis resistance may be attributable to downregulation of colony-stimulating factor 2. These findings provide mechanistic insight and identify targets that may be regulated by ovary-derived NE in early HGSC.
Insights
Norepinephrine (NE) promotes early high-grade serous carcinoma (HGSC) development by enabling preneoplastic lesions to become anchorage-independent. Blocking the beta-adrenergic receptor (β-AR) with propranolol prevents this NE-driven effect, suggesting new therapeutic targets.
Area of Science:
- Gynecologic Oncology
- Cancer Pathogenesis
- Tumor Microenvironment
Background:
- High-grade serous carcinoma (HGSC) is a lethal gynecological cancer with poor outcomes often due to late diagnosis and chemoresistance.
- Tumor innervation and the tumor microenvironment are increasingly recognized as critical factors in HGSC progression.
- Ovarian norepinephrine (NE) levels rise during ovulation and menopause, and NE is known to worsen advanced HGSC, but its role in early disease is unclear.
Purpose of the Study:
- To investigate the role of norepinephrine (NE) in the early pathogenesis of high-grade serous carcinoma (HGSC).
- To determine if NE instigates anchorage independence and micrometastasis of preneoplastic fallopian tube epithelium (FTE) lesions to the ovary.
Main Methods:
- Utilized fallopian tube epithelium (FTE) cell lines in ultra-low-attachment (ULA) culture to assess anchorage independence.
- Administered norepinephrine (NE) and employed β-adrenergic receptor (β-AR) blockers (propranolol) to evaluate receptor dependency.
- Analyzed the expression of colony-stimulating factor 2 (CSF2) to understand mechanisms of anoikis resistance.
Main Results:
- Norepinephrine (NE) treatment enabled FTE cells to survive in ULA culture, indicating anchorage independence, in a β-adrenergic receptor (β-AR)-dependent manner.
- The spheroid formation and cell viability induced by physiological NE were blocked by the β-AR antagonist propranolol.
- NE-induced anoikis resistance was associated with the downregulation of colony-stimulating factor 2 (CSF2).
Conclusions:
- Norepinephrine (NE) plays a crucial role in promoting early HGSC development by conferring anchorage independence to preneoplastic lesions.
- Targeting β-adrenergic receptors (β-ARs) or pathways involving CSF2 may offer novel strategies for HGSC prevention and interception.
- Ovary-derived NE may be a key regulator in the initial stages of HGSC pathogenesis.
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