Claudin-2 promotes colorectal cancer liver metastasis and is a biomarker of the replacement type growth pattern

Commun Biol. 2021 Jun 2;4(1):657. doi: 10.1038/s42003-021-02189-9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biomarkers, Tumor / antagonists & inhibitors
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / physiology*
  • Cell Adhesion / genetics
  • Cell Adhesion / physiology
  • Claudins / antagonists & inhibitors
  • Claudins / genetics
  • Claudins / physiology*
  • Colorectal Neoplasms / genetics
  • Colorectal Neoplasms / physiopathology
  • Colorectal Neoplasms / secondary*
  • Female
  • Gene Expression Regulation, Neoplastic
  • Gene Knockout Techniques
  • HT29 Cells
  • Hepatocytes / pathology
  • Heterografts
  • Humans
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / physiopathology
  • Lung Neoplasms / genetics
  • Lung Neoplasms / physiopathology
  • Lung Neoplasms / secondary
  • Mice
  • Mice, SCID
  • PDZ Domains / genetics
  • Prognosis
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism


  • Biomarkers, Tumor
  • CLDN2 protein, human
  • Claudins
  • RNA, Messenger
  • claudin 8