Cancer cell invasion is a key element in metastasis that requires integrins for adhesion/de-adhesion, as well as matrix metalloproteinases (MMPs) for focalized proteolysis. Herein we show that MMP-2 is up-regulated in resected colorectal tumors and degrades β1 integrins with the release of fragments containing the β1 I-domain. The β1 cleavage pattern is similar to that produced by digestion of α5β1 and α2β1 with MMP-2. Two such fragments, at 25 and 75 kDa, were identified after immunoprecipitation, with monoclonal antibody BD610468 reacting with the NH(2)-terminal I-like ectodomain followed by SDS-PAGE and microsequencing using electrospray (ISI-Q-TOF-Micromass) spectrometry. Cleavage of the β1 integrin can be abolished by inhibition of MMP-2 activity; it can be induced by up-regulation of MMP-2 expression, as exemplified by HT29 colon cancer cells transfected with pCMV6-XL5-MMP-2. Co-immunoprecipitation studies of colon cancer cells showed that the β1 integrin subunit is associated with MMP-2. The MMP-2-mediated shedding of the I-like domain from β1 integrins resulted in decreased adhesion of colon cancer cells to collagen and fibronectin, thus abolishing their receptivity. Furthermore, such cells showed enhanced motility as evaluated by a "wound healing-like" assay and time-lapse microscopy, indicating their increased invasiveness. Altogether, our data demonstrate that MMP-2 amplifies the motility of colon cancer cells, not only by digesting the extracellular matrix components in the vicinity of cancer cells but also by inactivating their major β1 integrin receptors.
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http://dx.doi.org/10.1074/jbc.M112.384909 | DOI Listing |
Inflamm Res
January 2025
Department of Biochemistry, Cancer Biology, Neuroscience, and Pharmacology, School of Medicine, Meharry Medical College, 1005 D.B. Todd Jr. Blvd, Nashville, TN, USA.
Background: The aberrant expression of α defensin 5 (DEFA5) protein in colonic inflammatory bowel diseases (IBDs) underlies the distinct pathogenesis of Crohn's colitis (CC). It can serve as a biomarker for differentiating CC from Ulcerative colitis (UC), particularly in Indeterminate colitis (IC) cases into UC and CC. We evaluated the specificity of commercially available anti-DEFA5 antibodies, emphasizing the need to further validate their appropriateness for a given application and highlighting the necessity for novel antibodies.
View Article and Find Full Text PDFFuture Oncol
August 2024
Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan.
J Anus Rectum Colon
January 2025
Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
Objectives: Although curative resection for synchronous peritoneal carcinomatosis has been reported to improve prognosis, cases with positive intraoperative lavage cytology have not been reported. In this study, we investigated the prognostic value of potentially curative resection based on colorectal cancer and lavage cytology positivity in patients with synchronous peritoneal carcinomatosis.
Methods: We retrospectively evaluated 72 patients who underwent intraoperative lavage cytology and one-stage potentially curative resection of primary and metastatic lesions (lavage cytology-positive, n = 21; lavage cytology-negative, n = 51) between July 2004 and December 2019.
J Anus Rectum Colon
January 2025
Department of Colorectal Surgery, National Cancer Center Hospital East, Chiba, Japan.
[This corrects the article DOI: 10.23922/jarc.2023-057.
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