ABSTRACT
Claudin-2 promotes breast cancer liver metastasis by enabling seeding and early cancer cell survival. We now demonstrate that Claudin-2 is functionally required for colorectal cancer liver metastasis and that Claudin-2 expression in primary colorectal cancers is associated with poor overall and liver metastasis-free survival. We have examined the role of Claudin-2, and other claudin family members, as potential prognostic biomarkers of the desmoplastic and replacement histopathological growth pattern associated with colorectal cancer liver metastases. Immunohistochemical analysis revealed higher Claudin-2 levels in replacement type metastases when compared to those with desmoplastic features. In contrast, Claudin-8 was highly expressed in desmoplastic colorectal cancer liver metastases. Similar observations were made following immunohistochemical staining of patient-derived xenografts (PDXs) that we have established, which faithfully retain the histopathology of desmoplastic or replacement type colorectal cancer liver metastases. We provide evidence that Claudin-2 status in patient-derived extracellular vesicles may serve as a relevant prognostic biomarker to predict whether colorectal cancer patients have developed replacement type liver metastases. Such a biomarker will be a valuable tool in designing optimal treatment strategies to better manage patients with colorectal cancer liver metastases.
Subject(s)
Biomarkers, Tumor/physiology , Claudins/physiology , Colorectal Neoplasms/secondary , Liver Neoplasms/pathology , Animals , Biomarkers, Tumor/antagonists & inhibitors , Biomarkers, Tumor/genetics , Cell Adhesion/genetics , Cell Adhesion/physiology , Claudins/antagonists & inhibitors , Claudins/genetics , Colorectal Neoplasms/genetics , Colorectal Neoplasms/physiopathology , Female , Gene Expression Regulation, Neoplastic , Gene Knockout Techniques , HT29 Cells , Hepatocytes/pathology , Heterografts , Humans , Liver Neoplasms/genetics , Liver Neoplasms/physiopathology , Lung Neoplasms/genetics , Lung Neoplasms/physiopathology , Lung Neoplasms/secondary , Mice , Mice, SCID , PDZ Domains/genetics , Prognosis , RNA, Messenger/genetics , RNA, Messenger/metabolismABSTRACT
Adherens (AJ) and tight junctions (TJ) maintain cell-cell adhesions and cellular polarity in normal tissues. Afadin, a multi-domain scaffold protein, is commonly found in both adherens and tight junctions, where it plays both structural and signal-modulating roles. Afadin is a complex modulator of cellular processes implicated in cancer progression, including signal transduction, migration, invasion, and apoptosis. In keeping with the complexities associated with the roles of adherens and tight junctions in cancer, afadin exhibits both tumor suppressive and pro-metastatic functions. In this review, we will explore the dichotomous roles that afadin plays during cancer progression.
