Elevated levels of TGFβ are a negative prognostic indicator for patients diagnosed with pancreatic cancer; as a result, the TGFβ pathway is an attractive target for therapy. However, clinical application of pharmacologic inhibition of TGFβ remains challenging because TGFβ has tumor suppressor functions in many epithelial malignancies, including pancreatic cancer. In fact, direct neutralization of TGFβ promotes tumor progression of genetic murine models of pancreatic cancer. Here, we report that neutralizing the activity of murine TGFβ receptor 2 using a monoclonal antibody (2G8) has potent antimetastatic activity in orthotopic human tumor xenografts, syngeneic tumors, and a genetic model of pancreatic cancer. 2G8 reduced activated fibroblasts, collagen deposition, microvessel density, and vascular function. These stromal-specific changes resulted in tumor cell epithelial differentiation and a potent reduction in metastases. We conclude that TGFβ signaling within stromal cells participates directly in tumor cell phenotype and pancreatic cancer progression. Thus, strategies that inhibit TGFβ-dependent effector functions of stromal cells could be efficacious for the therapy of pancreatic tumors. Cancer Res; 74(18); 1–12. ©2014 AACR.

HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur IKO mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apcmin/+ mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, HurIKO mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. HurIKO mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apcmin/+HurIKO were altered in AOM-DSS–treated HurIKO mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 1–14. ©2014 AACR.

Sarah Guy

Sarah Guy was diagnosed with stage III low-grade ovarian cancer in March 2011 and has since documented the restoration of her health on her blog. In this blog, she talks about the Walkabout program, a supportive care program for patients and care partners that combines mindfulness skills training with easy mindful walking outside, the use of digital photography and collage-making.

This past winter and spring was a heavy, formidable time for me. I was recovering from a bowel resection surgery, and while my body was healing, my oncologist and I were trying to plan my next course of treatment. I had so many questions, “Should I enroll in a trial? Which one? Where? Should I give the current treatment a little more time?” I was feeling confused, conflicted and fragile.

After leaving an oncology appointment, I noticed a Walkabout flyer in the waiting room. The words “walking,” “outside,” “art,” and “photography” stood out to me. It seemed like the perfect opportunity to do some exercise appropriate for my recovery while also processing my wide-ranging emotions. After an initial screening call with Caroline Peterson, the Walkabout program facilitator, I knew it was going to be a special program. She took the time to thoroughly explain the program goals and structure and to answer my questions. Her thoughtfulness and thoroughness appealed to my fragile state. It was a well cared-for program, and I was going to be well cared-for within it.

On the first day of the program, Caroline explained to us the evidence-based benefits of mindfulness, gave us an overview of the art materials and then guided us through making our first collage. Of the nine participants, seven of us had limited experience with art-making. She encouraged us to have fun and to play, and reminded us that there were no mistakes. Hers were words and instructions that I did not often hear within my cancer realm. So much of the cancer landscape is filled with battle language and imagery, and patients and doctors are continually confronted with high-stakes decisions and actions. But from day one in Walkabout, I heard “gentleness,” “kindness,” “play.” It was an environment that I welcomed and embraced.

During that first session, the only thing I felt compelled to do with the art materials was to create an image depicting a stable foundation and to organize the rest of the pieces in a symmetrical way. Upon looking at my completed work, I realized that my collage reflected my desires: I wanted order, structure, and stability in my life. I wanted a treatment plan in which everything fit nicely together.

During the subsequent sessions, Caroline introduced us to the attitudinal foundations of mindfulness practice: non-judging, patience, beginner’s mind, trusting ourselves, non-striving, acceptance, and letting be/letting go. Each week when making collages, if I let the collage unfold, if I implemented the attitudinal foundations, then the collage became a valuable source of personal insight. Within each collage I could see representations of my preoccupations and priorities. Collage-making became a tool to help me become aware of and understand my emotions and reactions.

After each week’s session, I shared photos of my collages with my family and friends, along with my interpretations of them. At times I’m concerned that loved ones get fatigued from hearing about my on-going treatments, but the collages were a fresh way to facilitate conversation. I was able to articulate and share deeper emotions in an accessible format, and my family and friends were very grateful that I shared my insights with them.

Initially, I valued Walkabout as a respite from daily distractions and the on-going high-stakes decisions and actions of cancer treatment. It was uninterrupted time for myself – time to get reacquainted with myself, to relax, to play. For those 2.5 hours each week, everything was taken care of. Caroline would greet us with a sincere, “How are you doing? So glad you are here.” Dinner was provided. Parking was paid for. And it was place to be with others who shared the values of mindfulness, who were on a similar journey, and who appreciated each other’s journey.

As the program went on, I found myself dedicating more time to creative projects, and it was becoming more natural for me to observe my thoughts, feelings, and reactions with less judgment and with more trust and patience. As I continue my cancer treatments, I now feel better equipped to handle the stress and decision-making processes, and to use my ability, as Caroline informed us, to confront the lion.

Walkabout sessions are just one of the many supportive services at the Abramson Cancer Center. Learn more about the Walkabout program here.

An unforeseen benefit of living with cancer is the intimacy it creates with individuals we barely know.