Interaction of RAGE with its ligands can promote tumor progression, invasion and angiogenesis. Although blocking RAGE signaling has been proposed as a potential anti-cancer strategy, functional contributions of RAGE expression in the tumor microenvironment (TME) has not been investigated in detail. Here, we evaluated the effect of genetic depletion of RAGE in TME on the growth of gliomas. In both invasive and non-invasive glioma models, animal survival was prolonged in RAGE knockout (Ager-/-) mice. However, the improvement in survival in Ager-/- mice was not due to changes in tumor growth rate but rather to a reduction in tumor-associated inflammation. Furthermore, RAGE ablation in the TME abrogated angiogenesis by downregulating the expression of pro-angiogenic factors which prevented normal vessel formation, thereby generating a leaky vasculature. These alterations were most prominent in non-invasive gliomas, where the expression of VEGF and pro-inflammatory cytokines were also
lower in tumor-associated macrophages (TAM) in Ager-/- mice. Interestingly, reconstitution of Ager-/- TAM with wild-type microglia or macrophages normalized tumor vascularity. Our results establish that RAGE signaling in glioma-associated microglia and TAM drives angiogenesis, underscoring the complex role of RAGE and its ligands in gliomagenesis.

Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor-suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming. Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry–based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high versus AKT1-high tumors, or in normal versus tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our findings show how prostate tumors undergo a metabolic reprogramming that reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics. Cancer Res; 74(24); 1–7. ©2014 AACR.

Cancer cells may overcome growth factor dependence by deregulating oncogenic and/or tumor suppressor pathways that affect their metabolism, or by activating metabolic pathways de novo with targeted mutations in critical metabolic enzymes. It is unknown whether human prostate tumors develop a similar metabolic response to different oncogenic drivers or a particular oncogenic event results in its own metabolic reprogramming.
Akt and Myc are arguably the most prevalent driving oncogenes in prostate cancer. Mass spectrometry-based metabolite profiling was performed on immortalized human prostate epithelial cells transformed by AKT1 or MYC, transgenic mice driven by the same oncogenes under the control of a prostate-specific promoter, and human prostate specimens characterized for the expression and activation of these oncoproteins. Integrative analysis of these metabolomic datasets revealed that AKT1 activation was associated with accumulation of aerobic glycolysis metabolites, whereas MYC overexpression was associated with dysregulated lipid metabolism. Selected metabolites that differentially accumulated in the MYC-high vs. AKT1-high tumors, or in normal vs. tumor prostate tissue by untargeted metabolomics, were validated using absolute quantitation assays. Importantly, the AKT1/MYC status was independent of Gleason grade and pathologic staging. Our findings show how prostate tumors undergo a metabolic reprogramming which reflects their molecular phenotypes, with implications for the development of metabolic diagnostics and targeted therapeutics.

This past Saturday, October 11th, hundreds of cyclists and their families geared up at a very cold and rainy starting line for the Structure Tone Ride to Conquer Cancer.

The nearly 150-mile ride was intense, invigorating, cathartic, full of fun and fellowship, and, most of all, provided a tremendous sense of community, comradely, and personal accomplishment. Over 500 riders finished the Ride to benefit Penn Medicine’s Abramson Cancer Center on a beautiful Sunday afternoon in Fairmount Park with Madlyn Abramson, her daughter Nancy and her two children, Stephanie and Rachel, and many other family and friends of the riders, cheering at the finish line. The Ride was phenomenal, and its success was a total team effort.

Thank you very much to all of our volunteers, staff, friends, family, and faculty for participating, helping, and contributing to the Ride.

A special thank you goes to our title sponsor, Structure Tone, and founding sponsor Ben Shein Law Offices.

Also, thanks to all the team members and captains for their dedication. The medical team led by Drs. Linda Jacobs and Alvin Wang was phenomenally helpful for many riders in need of treatment or wound care, including me. The development staff was terrific and special thanks goes to Karrie Borgelt for making it a wonderful event.

The feedback on peoples’ experiences with the Ride has been amazing. We have been successful in not only building our community spirit and engaging a new group of supporters, but also created an “esprit-de-corps,” as one department chair who rode told me. Cancer survivors from the Philadelphia area, as well as from as far as Canada shared their appreciation of what we are trying to accomplish.

And, Carl June rode with his team that included a colleague from Texas. The Ride has had a more far-reaching impact than we could ever have imagined.

Thank you everyone!! The Abramson Cancer Center team is not only innovating in research and clinical care, but also innovating new ways to engage our patients, their families, our community and new partners through new events such as the Ride. Stay tuned as we plan several new events for next year. Several of you have shared your own experiences of the ride, and we will be posting these in a new series on our Focus on Cancer blog. To share your experience, contact Michal Greenberg at [email protected].

Check out photos from the weekend here. Over the coming weeks, we’ll be posting more photos to Facebook, we encourage you to tag your photos with #TheRidePHL and tag Penn Medicine’s Abramson Cancer Center.

This past Saturday, October 11th, hundreds of cyclists and their families geared up at a very cold and rainy starting line for the Structure Tone Ride to Conquer Cancer.

The nearly 150-mile ride was intense, invigorating, cathartic, full of fun and fellowship, and, most of all, provided a tremendous sense of community, comradely, and personal accomplishment. Over 500 riders finished the Ride to benefit Penn Medicine’s Abramson Cancer Center on a beautiful Sunday afternoon in Fairmount Park with Madlyn Abramson, her daughter Nancy and her two children, Stephanie and Rachel, and many other family and friends of the riders, cheering at the finish line. The Ride was phenomenal, and its success was a total team effort.

Thank you very much to all of our volunteers, staff, friends, family, and faculty for participating, helping, and contributing to the Ride.

A special thank you goes to our title sponsor, Structure Tone, and founding sponsor Ben Shein Law Offices.

Also, thanks to all the team members and captains for their dedication. The medical team led by Drs. Linda Jacobs and Alvin Wang was phenomenally helpful for many riders in need of treatment or wound care, including me. The development staff was terrific and special thanks goes to Karrie Borgelt for making it a wonderful event.

The feedback on peoples’ experiences with the Ride has been amazing. We have been successful in not only building our community spirit and engaging a new group of supporters, but also created an “esprit-de-corps,” as one department chair who rode told me. Cancer survivors from the Philadelphia area, as well as from as far as Canada shared their appreciation of what we are trying to accomplish.

And, Carl June rode with his team that included a colleague from Texas. The Ride has had a more far-reaching impact than we could ever have imagined.

Thank you everyone!! The Abramson Cancer Center team is not only innovating in research and clinical care, but also innovating new ways to engage our patients, their families, our community and new partners through new events such as the Ride. Stay tuned as we plan several new events for next year. Several of you have shared your own experiences of the ride, and we will be posting these in a new series on our Focus on Cancer blog. To share your experience, contact Michal Greenberg at [email protected].

Check out photos from the weekend here. Over the coming weeks, we’ll be posting more photos to Facebook, we encourage you to tag your photos with #TheRidePHL and tag Penn Medicine’s Abramson Cancer Center.