<p>Pancreatic ductal adenocarcinoma (PDAC) is an
incredibly lethal disease with a 5-year survival rate of less than 8 percent in
the United States due to a lack of viable treatment options. The failures of chemo-
and radiotherapies have been linked to the heterogeneous nature of the tumor
microenvironment which forms a hypovascular, immunosuppressive and high coagulation
activity tissue. Indeed, PDAC patients have one of the highest rates of
thrombosis complications among all cancer types. The expression of two key
coagulation factors, Tissue Factor (TF) and Protease Activated Receptor 1
(PAR-1), have been associated with poor patient prognosis and aggressive cancer
progression. However, the molecular roles/mechanisms of TF and PAR-1 in PDAC
progression are not known. To establish how clotting factors (PAR-1, TF)
influence PDAC tumor progression, I utilized a genetically modified mouse model
(KPC) where <i>KRas<sup>G12D</sup></i> and <i>TRP53<sup>R172H</sup></i> mutations were
specifically introduced into mouse pancreas acinar cells to initiate PDAC
progression. Multiple primary mouse PDAC cell lines were generated and
characterized. TF and PAR-1 were highly expressed in primary KPC pancreatic
lesions, in PDAC tumors, and in KPC-derived cell lines, an expression profile
that is also observed in PDAC patient biopsies. In allograft studies, tumor
growth and metastatic potential were significantly diminished by shRNA
reduction of TF or PAR-1 in cancer cells or by genetic or pharmacological
reduction of the coagulation zymogen prothrombin in mice. Notably, PAR-1 deleted
KPC cells (KPC-Par-1<sup>KO</sup>) failed to generate sizable tumors; a
phenotype completely rescued by restoration of PAR-1 expression. To test the
significance of targeting PAR-1 in a clinical setting, PAR-1 expression was
withdrawn from established tumors to mimic a potential inhibitory effect of
PAR-1 on solid PDAC tumors. Removal of PAR-1 from tumors (11 days post
injection) yielded a diverse effect on tumor growth which can be categorized
into (i) a decline in tumor growth; (ii) continued tumor growth; and (iii)
stagnant tumor growth. Immunohistochemistry analysis of KPC2 shCon vs. shPar-1
subcutaneous allograft tumor samples revealed a massive immune cell
infiltration in KPC2 shPAR-1 tumors when compared to KPC2 shCon control tumors.
Accordingly, KPC-Par-1<sup>KO</sup> cells failed to form tumors in
immune-competent mice but displayed robust tumor growth in immune-compromised <i>NSG</i> mice, providing the first evidence
of a PAR-1 mediated tumor immune evasion pathway operating in PDAC. </p>
<p>Together, these results demonstrate that
PDAC disease is driven by activation of the coagulation system through tumor cell-derived TF, circulating prothrombin, and tumor
cell-derived PAR-1. These studies also
highlight a novel mechanism by which thrombin/PAR-1-mediated tumor growth
involves suppression of anti-tumor immunity in the tumor microenvironment. <b></b></p>
| Identifer | oai:union.ndltd.org:purdue.edu/oai:figshare.com:article/8029223 |
| Date | 16 October 2019 |
| Creators | Yi Yang (5930438) |
| Source Sets | Purdue University |
| Detected Language | English |
| Type | Text, Thesis |
| Rights | CC BY 4.0 |
| Relation | https://figshare.com/articles/THE_THROMBOSIS_PATHWAY_PROMOTES_PANCREATIC_CANCER_GROWTH_AND_METASTASIS/8029223 |
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