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Fibroblast Stromal Support Model for Predicting Human Papillomavirus-Associated Cancer Drug Responses
Abstract:
Currently, there are no specific antiviral therapeutic approaches targeting Human papillomaviruses (HPVs), which cause around 5% of all human cancers. Specific antiviral reagents are particularly needed for HPV-related oropharyngeal cancers (HPV+OPCs) whose incidence is increasing and for which there are no early diagnostic tools available. We and others have demonstrated that the estrogen receptor alpha (ERalpha) is overexpressed in HPV+OPCs, compared to HPV-negative cancers in this region, and that these elevated levels are associated with an improved disease outcome. Utilizing this HPV+ specific overexpression profile, we previously demonstrated that estrogen attenuates the growth and cell viability of HPV+ keratinocytes and HPV+ cancer cells in vitro. Expansion of this work in vivo failed to replicate this sensitization. The role of stromal support from the tumor microenvironment (TME) has previously been tied to both the HPV lifecycle and in vivo therapeutic responses. Our investigations revealed that in vitro co-culture with fibroblasts attenuated HPV+ specific estrogen growth responses. Continuing to monopolize on the HPV+ specific overexpression of ERalpha, our co-culture models then assessed the suitability of the selective estrogen receptor modulators (SERMs), raloxifene and tamoxifen, and showed growth attenuation in a variety of our models to one or both of these drugs in vitro. Utilization of these SERMs in vivo closely resembled the sensitization predicted by our co-culture models. Therefore, the in vitro fibroblast co-culture model better predicts in vivo responses. We propose that utilization of our co-culture in vitro model can accelerate cancer therapeutic drug discovery.
Insights
New research shows that co-culturing cancer cells with fibroblasts in vitro can predict how well estrogen receptor modulators will work against Human papillomavirus (HPV)-related cancers in vivo.
Area of Science:
- Oncology
- Virology
- Pharmacology
Background:
- Human papillomaviruses (HPVs) cause approximately 5% of human cancers, with a rising incidence of HPV-related oropharyngeal cancers (HPV+OPCs) lacking early diagnostic tools.
- Estrogen receptor alpha (ERalpha) is overexpressed in HPV+OPCs, correlating with better outcomes, and estrogen itself shows anti-cancer effects in vitro.
- Previous in vivo studies failed to replicate estrogen's anti-cancer effects, suggesting the tumor microenvironment (TME) plays a crucial role.
Purpose of the Study:
- To investigate the role of the tumor microenvironment, specifically fibroblasts, in modulating therapeutic responses in HPV+ oropharyngeal cancers.
- To evaluate the efficacy of selective estrogen receptor modulators (SERMs) like raloxifene and tamoxifen in preclinical models of HPV+OPCs.
- To determine if in vitro co-culture models can accurately predict in vivo therapeutic responses for HPV+ cancer drug discovery.
Main Methods:
- Established in vitro co-culture models of HPV+ oropharyngeal cancer cells with fibroblasts.
- Assessed the impact of estrogen and SERMs (raloxifene, tamoxifen) on cancer cell growth and viability in co-culture and single-culture settings.
- Validated in vitro findings through in vivo studies, comparing drug responses in animal models to those predicted by co-culture experiments.
Main Results:
- Fibroblast co-culture in vitro attenuated the anti-cancer effects of estrogen observed in single-culture models.
- Selective estrogen receptor modulators (SERMs), including raloxifene and tamoxifen, demonstrated growth-inhibitory effects in vitro across various models.
- In vivo responses to SERMs closely mirrored the sensitization patterns observed in the in vitro fibroblast co-culture models.
Conclusions:
- In vitro co-culture models incorporating fibroblasts provide a more accurate prediction of in vivo therapeutic responses compared to traditional in vitro methods.
- This co-culture approach can enhance the drug discovery process for novel cancer therapeutics targeting HPV+ cancers.
- Targeting the estrogen receptor pathway with SERMs shows promise for treating HPV+ oropharyngeal cancers.
