Abstract
The gut homing receptor integrin α4β7 is essential for the migration of pro-inflammatory T cells into the gut mucosa. Since intestinal neoplasia has been associated with chronic inflammation, we investigated whether interfering with gut-homing affects intestinal tumorigenesis. Using chemically induced and spontaneous intestinal tumor models we showed that lack of β7 integrin significantly impairs tumor growth without affecting tumor frequencies, with a mild translatable effect on overall survival. This correlates with human data showing lower MAdCAM-1 expression and disease-free survival in colorectal cancer patients. Thus, paradoxically in contrast to extra-intestinal tumors, blocking migration of immune cells into the gut might have a positive therapeutic effect on intestinal neoplasia.
Highlights
Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men around the world [1] [2]
CD25+ Foxp3+ regulatory T cells (TREG) can prevent the development of inflammation and intestinal cancer in two murine models [8, 9], suggesting that intestinal inflammation plays a key role in the pathogenesis of intestinal neoplasia
While T effector cells (TEFF) are typically protective against tumors in peripheral tissues, they paradoxically promote inflammation-driven neoplasia in the gut [11, 12]
Summary
Colorectal cancer (CRC) is the second most common cancer in women and the third most common in men around the world [1] [2]. Wild type or Itgb7-/-, mice received one intraperitoneal injection of AOM (Sigma Aldrich) at 10 mg/kg body weight followed by 3 cycles of DSS treatments (Fig 1). Mice were sacrificed and tumor analysis were done 10 weeks after AOM injection, corresponding to day 10 after 3 cycles of DSS treatment or after initial signs of distress, such as more than 15% of body weight loss, dehydration or hunched posture.
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