Colitis-associated cancer (CAC) is a complication of inflammatory bowel disease (IBD). Binding of extracellular ATP to the purinergic receptor P2RX7 has emerged as a critical event in controlling intestinal inflammation, acting to limit elevation of proinflammatory mast cells and cytokines and promote survival of regulatory T cells (Treg) and enteric neurons. In this study, we investigated the effect of P2RX7 blockade in an established mouse model of CAC. Using genetic and pharmacologic tools, we found unexpectedly that while P2RX7 mediated inflammatory responses, it also acted at an early time to suppress CAC development. P2RX7 blockade enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. The proliferative effects of P2RX7 blockade were associated with an increased production of TGFβ1 that was sufficient to stimulate the proliferation of intestinal epithelial cells. Finally, P2RX7 blockade also altered immune cell infiltration and promoted Treg accumulation within lesions of the digestive system. Taken together, our findings reveal an unexpected role for P2RX7 in preventing CAC, suggesting cautions in the use of P2RX7 inhibitors to treat IBD given the possibility of increasing risks CAC as a result. Cancer Res; 75(5); 1–11. ©2015 AACR.

Colitis-Associated Cancer (CAC), a complication of inflammatory bowel disease (IBD), is enhanced by chronic inflammation. Binding of extracellular ATP (eATP) to the purinergic P2X7 receptor (P2RX7) has recently emerged as a key signaling molecule in the control of intestinal inflammation by regulating cytokine production, regulatory T cell (Tregs) survival, mast cell-dependent intestinal inflammation and death of enteric neurons. In this study, we investigated the effect of P2RX7 blockade in a mouse model of dextran sodium sulfate-induced CAC. Using genetic and pharmacological tools, we demonstrated that while P2RX7 promoted an inflammatory response, it unexpectedly acted as a tumor suppressor during early CAC tumorigenesis. Indeed, we reported that the absence of P2RX7 activity enhanced proliferation of intestinal epithelial cells and protected them from apoptosis. Further, we demonstrated that P2RX7 blockade influenced immune cell infiltration and notably promoted Treg accumulation within lesions of the digestive system. Finally, we showed that P2RX7 inactivation increased TGFB1 (TGF-β1) production, which stimulated the proliferation of intestinal epithelial cells. Taken together, our findings define a novel and unexpected role for P2RX7 in protecting against CAC.

In 2011, Kimberly Fink was treated at the Abramson Cancer Center for uterine cancer. Once her treatment ended, Kimberly came up with the idea for TREATMiNT Box: a subscription based gift box for supporting patients during and after treatment.

Four years ago, Kimberly Fink traveled to Alabama to help her family clean up and rebuild after tornadoes had ripped apart her hometown.

She hadn’t been feeling well, and had spent the previous months getting tests, visiting doctors and asking for second opinions to figure out what was wrong.

But it was on this trip when her symptoms couldn’t be silenced.

“I was admitted to the emergency room, and they performed a battery of tests,” remembers Fink. The diagnosis was uterine cancer. At the time, she was only 33 years old.

“I asked the physician if he could recommend a cancer treatment center in Philadelphia, and he said that the Abramson Cancer Center was the best place to go,” says Fink. “He was right. As soon as I walked through the doors, I felt a sense of relief. I knew I was in the right place.”

Over the next full year, Fink received treatment, which included radiation and chemotherapy.

“Cancer treatment is a very isolating experience. Even though you are always surrounded by so many people, you can still feel very alone.”

Fink says that many people with cancer receive a lot of support and encouragement in the beginning of their treatment or when they are first diagnosed. But as weeks and months pass, support can wane – even though loved ones and friends have the best intentions.

It was this realization that inspired Fink to create TREATMiNT Box three years later.

Gifts that Keep On Giving

“TREATMiNT Box is a subscription gift box service for both people with cancer, as well as survivors,” says Fink. It is the first-ever subscription service specifically designed with this population in mind.

Each gift box is covered in inspirational messages and is sturdy enough to keep and hold mementos, cards or anything else. The boxes include a mix of practical gifts and inspirational items: gorgeous art prints, all-natural beauty products, cozy socks, organic scarves, tech goodies and fine paper products. There are boxes with separate gifts in mind for men as well as women, with gift boxes for boys and girls coming soon.

You can purchase a one-time gift box delivery or a monthly subscription for three, six or 12 months.

“TREATMiNT Box is a way you can send support love to someone with cancer and know they will be treated to special products to both comfort and inspire,” she says. “We want to provide a rock-solid way for friends and family to show their support and stay connected when it’s hard to relate.”

TREATMiNT Box is young – not even a year old – but has almost 300 subscribers so far. Fink says she plans to expand her services to include TREATMiNT boxes for kids and caregivers, as well as introduce a “Buy a box, donate a box” service. For every box purchased, Fink hopes to donate a box to someone in treatment.

“I want to continue to create a community of patients and survivors that help us curate products for our boxes,” says Fink. “Connecting with patients and survivors can be an extraordinary healing experience.”

Fink adds her own encouragement for those currently undergoing cancer treatment and therapy: “Stop Googling your cancer type and focusing on survival rates. Instead, focus on what you can do today to stay positive. Take things one day at a time.”

Hear Fink talk about TREATMiNT Box in the short video below.

Overexpression of HOXB7 in breast cancer cells induces an epithelial–mesenchymal transition and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here, we report that phosphorylation of SMAD3 was detected in a higher percentage in primary mammary tumor tissues from double-transgenic MMTV-Hoxb7/Her2 mice than tumors from single-transgenic Her2/neu mice, suggesting activation of TGFβ/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGFβ2 was high in four MMTV-Hoxb7/Her2 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, whereas TGFβ2 was low in HOXB7-depleted cells. HOXB7 directly bound to and activated the TGFβ2 promoter in luciferase and chromatin immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells were reversed by knockdown of TGFβ2 or pharmacologic inhibition of TGFβ signaling. Furthermore, knockdown of TGFβ2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor-associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGFβ2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGFβ2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell-autonomous and non–cell-autonomous manner through activation of the TGFβ signaling pathway. Cancer Res; 75(4); 1–11. ©2014 AACR.

Overexpression of HOXB7 in breast cancer cells induces an epithelial-mesenchymal transition (EMT) and promotes tumor progression and lung metastasis. However, the underlying mechanisms for HOXB7-induced aggressive phenotypes in breast cancer remain largely unknown. Here we report that phosphorylation of SMAD3 is detected in a higher percentage in primary mammary tumor tissues from double transgenic MMTV-HOXB7/Her2 mice than tumors from single transgenic Her2/neu mice, suggesting activation of TGF-β/SMAD3 signaling by HOXB7 in breast tumor tissues. As predicted, TGF-β2 was high in four mouse Her2xHOXB7 transgenic mouse tumor cell lines and two breast cancer cell lines transfected with HOXB7, while TGF-β2 was low in HOXB7-depleted cells. HOXB7 directly bound to, and activated the TGF-β2 promoter in luciferase and chromatin-immunoprecipitation assays. Increased migration and invasion as a result of HOXB7 overexpression in breast cancer cells was reversed by knockdown of TGF-β2 or pharmacologic inhibition of TGF-β signaling. Further, knockdown of TGF-β2 in HOXB7-overexpressing MDA-MB-231 breast cancer cells dramatically inhibited metastasis to the lung. Interestingly, HOXB7 overexpression also induced tumor associated macrophage (TAM) recruitment and acquisition of an M2 tumor-promoting phenotype. TGF-β2 mediated HOXB7-induced activation of macrophages, suggesting that TAMs may contribute to HOXB7-promoted tumor metastasis. Providing clinical relevance to these findings, by real-time PCR analysis, there was a strong correlation between HOXB7 and TGF-β2 expression in primary breast carcinomas. Taken together, our results suggest that HOXB7 promotes tumor progression in a cell autonomous and non-cell autonomous manner through activation of the TGF-β signaling pathway.