Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti‐angiogenic therapy. Surrogate biomarkers are not available to preoperatively identify patients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing. We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase‐like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF‐α. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4‐expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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.

Interstitial fluid pressure (IFP) distribution generated as a result of externally applied pressure (EAP) may play an important role in the etiology of decubitus ulcers. In the forelimbs of 10 thiopental sodium-anesthetized Yorkshire pigs, weighing 16-20 kg, we placed wick catheters 2-5 mm below the skin. After equilibration, we applied a pediatric cuff and added EAP. With zero EAP, the IFP was -3.9 +/- 1.4 (SD) mmHg. In each case of EAP, IFP as measured with the wick catheter increased and reached a plateau within 10-15 min. In normal tissues, IFP reached approximately 65-75% of EAP. When we created an edematous condition by preinfusing with excess saline, IFP was found to reach 100% of EAP. The total normal stress in the tissue, generated as a result of external cuff pressure, can be considered as a sum of interstitial fluid pressure and extranormal stress. Integrity of the fibrous network and pore fraction may be important in transmitting pressure to the fluid.

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