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TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.

ABSTRACT: Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was demonstrated in PC mouse models and patients. Using TIMP1-competent and TIMP1-deficient PC mouse models, we established a causal role of TIMP1 in determining shortened survival and increased liver metastasis in males. Observing TIMP1 expression as a risk parameter in males led to identification of a subpopulation exhibiting increased TIMP1 levels (T1HI males) in both primary tumors and blood. T1HI males showed increased risk for liver metastasis development not only in PC but also in colorectal cancer and melanoma. This study reveals a lifestyle-independent sex disparity in liver metastasis and may open new avenues toward precision medicine.

SUBMITTER: Hermann CD

PROVIDER: S-EPMC8480668 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

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TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.

Hermann Chris D CD Schoeps Benjamin B Eckfeld Celina C Munkhbaatar Enkhtsetseg E Kniep Lukas L Prokopchuk Olga O Wirges Nils N Steiger Katja K Häußler Daniel D Knolle Percy P Poulton Emily E Khokha Rama R Grünwald Barbara T BT Demir Ihsan Ekin IE Krüger Achim A

The Journal of experimental medicine 20210917 11

Sex disparity in cancer is so far inadequately considered, and components of its basis are rather unknown. We reveal that male versus female pancreatic cancer (PC) patients and mice show shortened survival, more frequent liver metastasis, and elevated hepatic metastasis-promoting gene expression. Tissue inhibitor of metalloproteinases 1 (TIMP1) was the secreted factor with the strongest male-biased expression in patient-derived pancreatic tumors. Male-specific up-regulation of systemic TIMP1 was ...[more]

PMID: 34533565

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Project description:ImportanceThe Model for End-stage Liver Disease (MELD)-based organ allocation system has significantly decreased mortality on the transplant waiting list for patients with end-stage liver disease. However, women have remained at a disadvantage with respect to access to deceased donor liver transplant (DDLT) even after introduction of the MELD score for organ allocation.ObjectiveTo determine whether availability of living donation in a transplant program can offset inequity in liver transplant (LT) allocation for women.Design, setting, and participantsThis cohort study retrospectively analyzed adult patients listed for LT at the University Health Network in Toronto, Ontario, Canada. Patients included had a potential living donor (pLD) at the moment of listing. This study was performed from November 13, 2012, to May 31, 2019. A total of 1289 listed patients (830 men; 459 women) were analyzed during the study period.Main outcomes and measuresThis study performed survival analysis and competing-risk analysis to delineate how access to livers from living donors was associated with events in women vs men on the transplant waiting list (LT, death, or dropout).ResultsOf 1289 included patients, 459 (35.6%) were women, and the mean (SD) age was 56.1 (10.0) years at assessment and listing. A total of 783 of 1289 listed patients underwent LT. Among those with no pLD at assessment, there was a higher median (range) Model for End-stage Liver Disease incorporating sodium levels (MELD-Na) score at listing (22 [6-50] vs 19 [6-50]; P < .001) and at LT (27 [6-49] vs 20 [6-52]; P < .001) in women receiving DDLT. Women were at a significant disadvantage without a pLD (hazard ratio [HR], 1.29; 95% CI, 1.04-1.60; P = .01); there was no difference in access to LT with availability of a pLD (HR, 0.93; 95% CI, 0.76,-1.14; P = .44). The instantaneous rate of receiving a transplant in men with a pLD was 1.39 times higher than men who did not have a pLD (HR, 1.39; 95% CI; P < .001) and the instantaneous rate of receiving a transplant in women with a pLD was 1.92 times higher than in women who did not (HR, 1.92; 95% CI, 1.51-2.44; P < .001). The HR was 1.38 times higher in women compared with men across the MELD-Na score strata (HR, 1.38; 95% CI, 1.03-1.84; P = .03) and 2.04 times higher when the MELD-Na score was less than 20 (HR, 2.04; 95% CI, 1.31-3.14; P = .001).Conclusions and relevanceThese study findings suggest that women can overcome the complex problem of allocation inequity with access to livers from living donors. Women with access only to DDLT were much more unwell than men independent of liver disease at the time of listing, dropout, or LT. Therefore, the wider availability of living donation liver transplant would be helpful in addressing the sex disparity in access to LT in the current MELD-Na era.

Dataset Information

TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.

Publications

TIMP1 expression underlies sex disparity in liver metastasis and survival in pancreatic cancer.

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