The Microenvironment Controls CDX2 Homeobox Gene Expression in Colorectal Cancer Cells

Abstract

The homeobox gene CDX2 plays a major role in development, especially in the gut, and it also acts as a tumor suppressor in the adult colon. Using orthotopic and heterotopic xenografts of human primary colorectal tumor cells and cell lines in nude mice, we addressed the effect of the microenvironment on CDX2 expression. In cells expressing CDX2 at a high level in culture, this level was maintained in subcutaneous grafts but was reduced when implanted into the cecum wall. Reciprocally, in cells with low CDX2 expression in culture, the level remained low in grafts into the cecum wall but was stimulated subcutaneously. In vitro co-cultures showed that CDX2 expression was activated in cells grown on layers of skin fibroblasts but not on intestinal fibroblasts. The stimulation was transcriptional, as assessed by transfection experiments with reporter plasmids containing the murine Cdx2 promoter. Together, these data demonstrate experimentally that CDX2 expression is adaptable and strongly dependent on the microenvironment surrounding the tumor cells. We exclude a role of the Notch pathway in this regulation. The regulation of CDX2 by the microenvironment might be relevant during the process of metastatic dissemination when the gene is transiently turned down in invasive cells. Colorectal cancer (CRC) is a major problem of public health because of its severity and high incidence. The severity is mainly attributable to the propensity of tumor cells to invade the stroma and eventually to disseminate into metastases. It is generally thought that the progression along the adenoma, carcinoma, metastasis sequence is accompanied by the accumulation of an increasing number of irreversible genomic alterations.1 In addition, reversible changes induced by the microenvironment facing malignant cells are also considered to be of prime importance for tumor cell invasion and metastatic dissemination.2 For instance, the epithelial-mesenchymal transition is a hallmark of invasive cells that escape the primary tumor, whereas the circulating tumor cells can undergo mesenchymal-epithelial transition at the homing site to form metastases.The major reversible changes reported in invasive cells spreading out from primary tumors include the decrease of membranous E-cadherin, the massive nuclear translocation of ␤-catenin, the activation of the cell cycle inhibitor p16, and the intracellular accumulation of the basement membrane molecule laminin-␥2. 2 Recently, a careful analysis of primary CRCs and liver metastases led us to show that invasive CRC cells are also characterized by a reversible decline of the intestine-specific homeoprotein CDX2.3 CDX2 is a transcription factor that plays a central role in embryos to define the organ-specific identity of the presumptive gut endoderm. 4 -7 At the adult stage, it belongs to the network that controls proliferation and differentiation of the continuously renewing gut epithelium.8,9 CDX2 also has a tumor suppressor function in the colon, because Cdx2 ϩ/Ϫ mice are hypersensitive to CRC progression in...

The intestine-specific homeobox gene Cdx2 decreases mobility and antagonizes dissemination of colon cancer cells

“…Given that constitutively active b-catenin does not directly regulate the Cdx2 promoter (Domon-Dell and Freund, 2002) and that Sox9, a target of b-catenin/ TCF4 that inhibits Cdx2 (Blache et al, 2004), is not upregulated during in vitro wound healing, the decline of Cdx2 in migrating cells may not depend on b-catenin. We reported previously that Cdx2 expression depends on the microenvironment and is downregulated by collagen type I via integrin-b1 and FAK (Brabletz et al, 2004;Benahmed et al, 2007). Interestingly, we show here that Integrin-b1 is upregulated during wound healing.…”

CaSR stimulates secretion of Wnt5a from colonic myofibroblasts to stimulate CDX2 and sucrase-isomaltase using Ror2 on intestinal epithelia

“…In fact, little is known about the regulation of CDX2 activity. Definitive studies have shown that phosphorylation of CDX2, by p38 MAP kinase, will regulate its transcriptional activity and modulate its interactions with other cofactors (8,11,12,33,35,64). The targeted degradation of CDX2 following its phosphorylation by Cdk2 has demonstrated that CDX2 homeostasis may be regulated by cell cycle machinery (12).…”

The clinical perspectives of CDX2 expression in colorectal cancer: A qualitative systematic review

“…A study engrafting human colon cancers, freshly surgically resected, into the subcutis and the cecal wall of nude-mice, showed differential expression pattern with regard to the site of implantation [74]. Thus, the tumors showed a heterogeneous expression pattern at the time of surgical resection, but when subcutaneous injected into the mice, an increased homogeneous expression was observed.…”