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Suppression of pancreatic cancer liver metastasis by secretion-deficient ITIH5
Eric D Young1, Sharon J Manley1, Thomas C Beadnell1
1Department of Cancer Biology, University of Kansas Medical Center, Kansas City, KS, USA.
Background:
Previously, we identified ITIH5 as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis in experimental models. Expression of ITIH5 correlated with decreased cell motility, invasion and metastasis without significant inhibition of primary tumour growth. Here, we tested whether secretion of ITIH5 is required to suppress liver metastasis and sought to understand the role of ITIH5 in human PDAC.
Methods:
We expressed mutant ITIH5 with deletion of the N-terminal secretion sequence (ITIH5Δs) in highly metastatic human PDAC cell lines. We used a human tissue microarray (TMA) to compare ITIH5 levels in uninvolved pancreas, primary and metastatic PDAC.
Results:
Secretion-deficient ITIH5Δs was sufficient to suppress liver metastasis. Similar to secreted ITIH5, expression of ITIH5Δs was associated with rounded cell morphology, reduced cell motility and reduction of liver metastasis. Expression of ITIH5 is low in both human primary PDAC and matched metastases.
Conclusions:
Metastasis suppression by ITIH5 may be mediated by an intracellular mechanism. In human PDAC, loss of ITIH5 may be an early event and ITIH5-low PDAC cells in primary tumours may be selected for liver metastasis. Further defining the ITIH5-mediated pathway in PDAC could establish future therapeutic exploitation of this biology and reduce morbidity and mortality associated with PDAC metastasis.
Insights
The protein ITIH5 suppresses pancreatic ductal adenocarcinoma (PDAC) liver metastasis, even without secretion. Loss of ITIH5 in PDAC may promote metastasis, suggesting therapeutic potential.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Metastasis
Background:
- ITIH5 (Inter-alpha-trypsin inhibitor heavy chain family member 5) identified as a suppressor of pancreatic ductal adenocarcinoma (PDAC) metastasis.
- ITIH5 expression correlates with reduced cell motility, invasion, and metastasis in experimental models.
- Study investigates the role of ITIH5 secretion in suppressing liver metastasis and its function in human PDAC.
Purpose of the Study:
- To determine if ITIH5 secretion is necessary for suppressing liver metastasis in PDAC.
- To elucidate the intracellular role of ITIH5 in PDAC metastasis.
- To analyze the expression levels of ITIH5 in human PDAC tissues and metastases.
Main Methods:
- Engineered secretion-deficient ITIH5 (ITIH5Δs) in metastatic human PDAC cell lines.
- Utilized human tissue microarrays (TMA) to compare ITIH5 expression in normal pancreas, primary PDAC, and metastatic PDAC.
- Assessed the impact of ITIH5Δs on cell morphology, motility, and liver metastasis suppression.
Main Results:
- Secretion-deficient ITIH5Δs effectively suppressed liver metastasis, similar to secreted ITIH5.
- Expression of ITIH5Δs was linked to rounded cell morphology and reduced cell motility.
- ITIH5 expression is significantly low in both primary human PDAC and matched metastatic lesions.
Conclusions:
- ITIH5-mediated suppression of metastasis may occur via an intracellular mechanism.
- Loss of ITIH5 appears to be an early event in human PDAC development.
- ITIH5-low PDAC cells may be selected for liver metastasis, highlighting potential therapeutic targets.
