Hepatocyte growth factor/MET and CD44 in colorectal cancer: partners in tumorigenesis and therapy resistance.

Intestinal epithelial self-renewal is a tightly controlled process, which is critically dependent on WNT signalling. Aberrant activation of the WNT pathway in intestinal stem cells (ISCs) results in constitutive transcription of target genes, which collectively drive malignant transformation in colorectal cancer (CRC). However, the contribution of individual genes to intestinal homeostasis and tumorigenesis often is incompletely defined.

MET Signaling Mediates Intestinal Crypt-Villus Development, Regeneration, and Adenoma Formation and Is Promoted by Stem Cell CD44 Isoforms.

Background & Aims: Resistance of metastatic human colorectal cancer cells to drugs that block epidermal growth factor (EGF) receptor signaling could be caused by aberrant activity of other receptor tyrosine kinases, activating overlapping signaling pathways. One of these receptor tyrosine kinases could be MET, the receptor for hepatocyte growth factor (HGF). We investigated how MET signaling, and its interaction with CD44 (a putative MET coreceptor regulated by Wnt signaling and highly expressed by intestinal stem cells [ISCs] and adenomas) affects intestinal homeostasis, regeneration, and adenoma formation in mini-gut organoids and mice.

Aberrantly expressed LGR4 empowers Wnt signaling in multiple myeloma by hijacking osteoblast-derived R-spondins.

The unrestrained growth of tumor cells is generally attributed to mutations in essential growth control genes, but tumor cells are also affected by, or even addicted to, signals from the microenvironment. As therapeutic targets, these extrinsic signals may be equally significant as mutated oncogenes. In multiple myeloma (MM), a plasma cell malignancy, most tumors display hallmarks of active Wnt signaling but lack activating Wnt-pathway mutations, suggesting activation by autocrine Wnt ligands and/or paracrine Wnts emanating from the bone marrow (BM) niche.

CD44-deficiency attenuates the immunologic responses to LPS and delays the onset of endotoxic shock-induced renal inflammation and dysfunction.

Acute kidney injury (AKI) is a common complication during systemic inflammatory response syndrome (SIRS), a potentially deadly clinical condition characterized by whole-body inflammatory state and organ dysfunction. CD44 is a ubiquitously expressed cell-surface transmembrane receptor with multiple functions in inflammatory processes, including sterile renal inflammation. The present study aimed to assess the role of CD44 in endotoxic shock-induced kidney inflammation and dysfunction by using CD44 KO and WT mice exposed intraperitoneally to LPS for 2, 4, and 24 hours .

CD44 expression in intestinal epithelium and colorectal cancer is independent of p53 status.

CD44 marks stem cell-like cells in a number of tumour types, including colorectal cancer (CRC), while aberrant CD44 expression conveys increased tumourigenic, invasive, and metastatic potential. Previous data indicate that CD44 is a direct target of p53-mediated transcriptional repression in breast cancer. Since inactivating p53 mutations are frequent genetic events in CRC these could unleash expression of CD44.

Distinct CD44 splice variants differentially affect collateral artery growth.

Objective: Lack of the adhesion molecule CD44 reduces collateral artery growth (arteriogenesis) in a murine hindlimb model. CD44 function is influenced by expression of 10 alternatively spliced exons (v1-v10), with unknown effects on arteriogenesis. As the variant exon CD44v3 binds heparan sulphate and facilitates preservation of growth factors, we hypothesized that the variably spliced exon region of CD44, especially exon CD44v3, is involved in arteriogenesis.

WNT signaling controls expression of pro-apoptotic BOK and BAX in intestinal cancer.

In a majority of cases, colorectal cancer is initiated by aberrant activation of the WNT signaling pathway. Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or β-catenin causes constitutively active β-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to cancer precursor lesions, called dysplastic aberrant crypt foci. Deregulated apoptosis is a hallmark of adenomatous colon tissue.

Deletion of the WNT target and cancer stem cell marker CD44 in Apc(Min/+) mice attenuates intestinal tumorigenesis.

Mutation of the genes encoding the WNT signaling components adenomatous polyposis coli or beta-catenin plays a critical role in the initiation of colorectal cancer. These mutations cause constitutively active beta-catenin/TCF-mediated transcription, driving the transformation of intestinal crypts to colorectal cancer precursor lesions, called dysplastic aberrant crypt foci. CD44 is a prominent WNT signaling target in the intestine and is selectively expressed on the renewing epithelial cells lining the crypts.

Activation of Wnt signaling in the intestinal mucosa of Apc +/min mice does not cause overexpression of the receptor tyrosine kinase Met.

The receptor tyrosine kinase MET is overexpressed in human colorectal adenomas and carcinomas, suggesting an instrumental role for MET signaling in the onset and progression of colorectal cancer. To corroborate this role, animal models are needed. To study the expression of Met in the normal and neoplastic mouse intestine, we generated an Armenian hamster monoclonal antibody against mouse Met.