Metabolic rearrangements subsequent to malignant transformation are not well characterized in endometrial cancer (EC). Identification of altered metabolites could facilitate imaging-guided diagnosis, treatment surveillance and help to identify new therapeutic options. Here we employed high resolution-magic angle spinning magnetic resonance mass spectroscopy on EC surgical specimens and normal endometrial tissue to investigate key modulators that might explain metabolic changes, incorporating additional investigations using qRT-PCR, Western blotting, tissue microarrays and uptake assays of [3H]-labeled choline. Lipid metabolism was severely dysregulated in EC with various amino acids, inositols, nucleobases and glutathione also altered. Among the most important lipid-related alterations was increased phosphocholine levels (increased 70% in EC). Mechanistic investigations revealed that changes were not due to altered choline transporter expression, but rather increased expression of choline kinase α (CHKA) and an activated deacylation pathway, as indicated by upregulated expression of the catabolic enzymes LYPLA1, LYPLA2 and GPCPD1. We confirmed the significance of CHKA overexpression on a tissue microarray including a large series of endometrial hyperplasia, atypical hyperplasia and adenocarcinoma tissues, supporting a role for CHKA in malignant transformation. Lastly, we documented several-fold increases in the uptake of [3H]choline in endometrial cancer cell lines compared to normal endometrial stromal cells. Our results validate deregulated choline biochemistry as an important source of non-invasive imaging biomarkers for EC.

“I think that anyone who has received a cancer diagnosis would agree that it is a moment which is life-altering: emotions range from fear and sadness, to anger and regret, after which you can’t help but see everything in a different light.”

For Sara Gowing, that new light as a breast cancer survivor has been characterized by elation for her cancer remission and good health against the odds of and fear for her cancer returning.

“As my breast cancer treatment came to an end, I learned that palpation would be my primary method for monitoring recurrence,” Sara explained. “I was startled to think that after spending a year undergoing cutting edge treatments that included surgery, rounds of chemotherapy with two different drugs, and radiation, I would be back to relying upon breast exams to catch a recurrence of the cancer.”

Angela DeMichele, MD, MSCE (center) with Sara Gowing and her husband Jim, at the celebration of Dr. DeMichele’s appointment as the Alan and Jill Miller Associate Professor in Breast Cancer Excellence.

Seeking an Active Measure for Recurrence in Post-treatment Survivorship

Despite 5-year survival rates approaching 90%, a substantial number of breast cancer patients relapse – and many more experience late treatment effects or are diagnosed with a second cancer. As a consequence, millions of breast cancer survivors find themselves in a post-treatment survivorship period that is largely devoid of active measures that they can take to monitor and prevent recurrence.

Sara asked her oncologist, and co-leader of the Breast Cancer Research Program, Angela DeMichele, MD, MSCE, what she could do to help propel breast cancer recurrence research forward.

“I got to know Dr. DeMichele particularly well during my chemotherapy. She was such a big help and provided so much reassurance during the unknowns surrounding my treatment,” Sara explained.

Forming the 2-PREVENT Translational Center of Excellence

The Gowings generously established the Breast Cancer Recurrence Program in support of the 2-PREVENT Translational Centers of Excellence (TCE) at the Abramson Cancer Center, co-led by Dr. DeMichele and Lewis Chodosh, MD, PhD, Professor and Chair of the Department of Cancer Biology, Perelman School of Medicine. Translational Centers of Excellence are virtual centers that bring the most brilliant minds across Penn’s medical campus together, to solve cancer’s most complex challenges.

The 2-PREVENT TCE focuses on the microscopic cells that are left in the body after cancer treatment—rather than the original tumor—and researches how they relate to the original tumor, where they live, how they grow and how they relate to the relapsed tumor. That information is then used to develop clinical trials focused on innovative, targeted therapies.

These cross-disciplinary teams are already making great progress, helping deliver novel, personalized cancer care to cancer patients.

Sara has joined the ranks of the Abramson Cancer Center’s brave patients, advocates, and philanthropists who have formed a community of support in the fight to advance research that offers better options and therapies for women diagnosed with breast cancer.

“I am so pleased to be able to support the amazing work being done at the Abramson Cancer Center and know that we will be able to find a cure for breast cancer. Forever.”

“I think that anyone who has received a cancer diagnosis would agree that it is a moment which is life-altering: emotions range from fear and sadness, to anger and regret, after which you can’t help but see everything in a different light.”

For Sara Gowing, that new light as a breast cancer survivor has been characterized by elation for her cancer remission and good health against the odds of and fear for her cancer returning.

“As my breast cancer treatment came to an end, I learned that palpation would be my primary method for monitoring recurrence,” Sara explained. “I was startled to think that after spending a year undergoing cutting edge treatments that included surgery, rounds of chemotherapy with two different drugs, and radiation, I would be back to relying upon breast exams to catch a recurrence of the cancer.”

Seeking an Active Measure for Recurrence in Post-treatment Survivorship

Despite 5-year survival rates approaching 90%, a substantial number of breast cancer patients relapse – and many more experience late treatment effects or are diagnosed with a second cancer. As a consequence, millions of breast cancer survivors find themselves in a post-treatment survivorship period that is largely devoid of active measures that they can take to monitor and prevent recurrence.

Sara asked her oncologist, and co-leader of the Breast Cancer Research Program, Angela DeMichele, MD, MSCE, what she could do to help propel breast cancer recurrence research forward.

“I got to know Dr. DeMichele particularly well during my chemotherapy. She was such a big help and provided so much reassurance during the unknowns surrounding my treatment,” Sara explained.

Forming the 2-PREVENT Translational Center of Excellence

The Gowings generously established the Breast Cancer Recurrence Program in support of the 2-PREVENT Translational Centers of Excellence (TCE) at the Abramson Cancer Center, co-led by Dr. DeMichele and Lewis Chodosh, MD, PhD, Professor and Chair of the Department of Cancer Biology, Perelman School of Medicine. Translational Centers of Excellence are virtual centers that bring the most brilliant minds across Penn’s medical campus together, to solve cancer’s most complex challenges.

The 2-PREVENT TCE focuses on the microscopic cells that are left in the body after cancer treatment—rather than the original tumor—and researches how they relate to the original tumor, where they live, how they grow and how they relate to the relapsed tumor. That information is then used to develop clinical trials focused on innovative, targeted therapies.

These cross-disciplinary teams are already making great progress, helping deliver novel, personalized cancer care to cancer patients.

Sara has joined the ranks of the Abramson Cancer Center’s brave patients, advocates, and philanthropists who have formed a community of support in the fight to advance research that offers better options and therapies for women diagnosed with breast cancer.

“I am so pleased to be able to support the amazing work being done at the Abramson Cancer Center and know that we will be able to find a cure for breast cancer. Forever.”

Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived “colonosphere” cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis, and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multilineage differentiation, proliferation, and tumor growth without reducing the tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively correlated with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity, but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity. Cancer Res; 74(22); 1–14. ©2014 AACR.

Colorectal tumorigenesis is accompanied by the generation of oxidative stress, but how this controls tumor development is poorly understood. Here, we studied how the H2O2-reducing enzyme glutathione peroxidase 2 (GPx2) regulates H2O2 stress and differentiation in patient-derived ‘colonosphere’ cultures. GPx2 silencing caused accumulation of radical oxygen species, sensitization to H2O2-induced apoptosis and strongly reduced clone- and metastasis-forming capacity. Neutralization of radical oxygen species restored clonogenic capacity. Surprisingly, GPx2-suppressed cells also lacked differentiation potential and formed slow-growing undifferentiated tumors. GPx2 overexpression stimulated multi-lineage differentiation, proliferation and tumor growth without reducing tumor-initiating capacity. Finally, GPx2 expression was inversely correlated with H2O2-stress signatures in human colon tumor cohorts, but positively with differentiation and proliferation. Moreover, high GPx2 expression was associated with early tumor recurrence, particularly in the recently identified aggressive subtype of human colon cancer. We conclude that H2O2 neutralization by GPx2 is essential for maintaining clonogenic and metastatic capacity but also for the generation of differentiated proliferating tumor mass. The results reveal an unexpected redox-controlled link between tumor mass formation and metastatic capacity.