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The homeobox transcription factor Cdx2 specifies intestinal development and homeostasis and is considered a tumor suppressor in colorectal carcinogenesis. However, Cdx2 mutations are rarely found. Invasion of colorectal cancer is characterized by a transient loss of differentiation and nuclear accumulation of the oncoprotein ␤-catenin in budding tumor cells. Strikingly, this is reversed in growing metastases, indicating that tumor progression is a dynamic process that is not only driven by genetic alterations but also regulated by the tumor environment. Here we describe a transient loss of Cdx2 in budding tumor cells at the tumor host interface, and reexpression of Cdx2 in metastases. Cell culture experiments show that collagen type I, through ␤ 1 integrin signaling, triggers a transient transcriptional down-regulation of Cdx2 and its intestine-specific target gene sucrase isomaltase, associated with a loss of differentiation. These data indicate an active role for the tumor environment in malignant tumor progression.

Studies suggest a variety of biological effects of soybean isoflavones, but there is little information regarding small intestinal absorption and metabolism. The aim of this study was to investigate intestinal handling of luminally administered soybean-based tofu in an isolated preparation of the luminally and vascularly perfused rat small intestine (male Sprague-Dawley, approximately 45 d old). A synthetic emulsion free from blood components was used as vascular medium, with a perfluorocarbon as oxygen carrier. Luminal media consisted of tofu, predigested with pepsin and pancreatin and emulsified with bile acids, containing 39. 5 micromol/L genistein compounds and 19.1 micromol/L daidzein compounds. Viability of the organ preparation was maintained during the entire perfusion, confirmed by lack of significant differences between tofu and control perfusion experiments for arterial pressure, glucose consumption, oxygen uptake, lactate-pyruvate ratio and acid-base homeostasis. Daidzein (8.9%) and genistein (8.0%) compounds from tofu exhibited almost the same (P: > 0.05) absorption rate during small intestinal passage. The majority of the absorbed genistin appeared vascularly as genistein (4.4%), in addition to minor amounts of unchanged genistin (2.1%) and genistein glucuronide (1.5%). In the luminal effluent, a considerable increase of genistein (338%) as well as daidzein (190%) as cleavage products of the glucosides and malonyl-glucosides was observed. The distribution of daidzein compounds in the small intestine was not different from that of genistein compounds (P: > 0.05), except for the blood vessels, which had extremely low total amounts. Sulfate derivatives of genistein and daidzein compounds were not detectable. An effect of tofu ingredients was observed on absorption rate of genistin, on glucuronidation and on distribution of genistein glucuronide in the intestine.

Uptake and intestinal metabolism of physiologically active genistin were studied in an ex vivo intestinal perfusion model; luminally applied concentrations were 5.9, 12.0, and 23.8 W Wmol/l. The intestinal absorption of genistin was 14.9% ( þ 2.3, n = 9), irrespective of the amounts applied. The majority of the absorbed genistin appeared as genistein glucuronide (11.6%), also recovered as the main metabolite on the luminal side (19.5%). Minor amounts of genistin (1.3%) and genistein (1.9%) were found on the vascular side, whereas 15.4% of applied genistin was luminally cleaved to yield genistein. Sulfate derivatives of genistein or genistin were not observed. ß

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