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

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.

COX5B-Mediated Bioenergetic Alterations Modulate Cell Growth and Anticancer Drug Susceptibility by Orchestrating Claudin-2 Expression in Colorectal Cancers

“…Subsequent experiments further confirmed this result ( Figure 5 ), supporting that COX5B is positively correlated with CLDN2 expression in CRCs. CLDN2 is a promising tight junction localized protein with well-characterized functions, including promoting the tumorigenicity, metastasis, and susceptibility of cells to 5-FU, perhaps through ameliorating cancer stem cell property in CRCs [ 36 , 37 , 38 ]. Our findings partially reflect that CLDN2 acts as an effector downstream of COX5B-induced control of cell proliferation and sensitivity to anticancer drugs ( Figure 6 ).…”

Extracellular Vesicle Antibody Microarray for Multiplexed Inner and Outer Protein Analysis

“…The outer proteins were all membrane proteins, and include the three tetraspanins used for capture (CD9, CD63, CD81) as well as CD82, another tetraspanin and known tumor metastasis suppressor; 52 and the integrin (ITG) subunits (α2, α6, β1, β4) 8 that have been associated with EV-mediated metastatic organotropism. 8 Among the inner proteins was the tight junction protein claudin-2, 53 a prognosis biomarker of replacement-type liver metastasis in EVs from CRC patients, 54 detected through its cytoplasmic domain, and cytosolic proteins, which were selected based on known and widespread association with EVs. 55 They included the heat-shock proteins (HSP90, HSP70), 56 and ESCRT-associated protein Alix, which is involved in EV biogenesis and cargo sorting.…”

Dissecting the Mechanism of Action of Spiperone—A Candidate for Drug Repurposing for Colorectal Cancer

“…In addition to UPR activation, RNA-Seq analysis revealed that the most common significantly downregulated genes were associated with cancer cell proliferation and invasiveness. For example, CLDN2 expression was recently linked to increased incidence of CRC-associated liver metastasis [165], whereas CXCR4 [63] and CYP24A1 [64] are increasingly recognized as prognostic markers for CRC progression. PIF1 downregulation is usually associated with decreased survival in neoplastic cells, but not in nonmalignant cells [60], whereas PSRC1 has been confirmed to be involved in microsatellite instability (MSI)-a genetic condition resulting from incompetent DNA mismatch repair, and frequently associated with CRC incidence and progression [166].…”