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Hyaluronidase-Expressing Salmonella Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma.

ABSTRACT: In pancreatic ductal adenocarcinoma (PDAC), the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic drugs and cytotoxic immune subsets to penetrate and eliminate tumors. The dense stromal matrix protecting cancer cells, also known as desmoplasia, results from the overproduction of major ECM components such as collagens and hyaluronic acid (HA). Although candidate drugs targeting ECM components have shown promise in increasing penetration of chemotherapeutic agents, severe adverse effects associated with systemic depletion of ECM in peripheral healthy tissues limits their use at higher, more effective doses. Currently, few strategies exist that preferentially degrade ECM in tumor tissue over healthy tissues. In light of this, we have developed an attenuated, tumor-targeting Salmonella typhimurium (ST) expressing functional bacterial hyaluronidase (bHs-ST), capable of degrading human HA deposited within PDAC tumors. Our data show that bHs-ST (i) targets and colonizes orthotopic human PDAC tumors following systemic administration and (ii) is efficiently induced in vivo to deplete tumor-derived HA, which in turn (iii) significantly increases diffusion of Salmonella typhimurium within desmoplastic tumors. BHs-ST represents a promising new tumor ECM-targeting strategy that may be instrumental in minimizing off-tumor toxicity while maximizing drug delivery into highly desmoplastic tumors.

SUBMITTER: Ebelt ND

PROVIDER: S-EPMC7007852 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Hyaluronidase-Expressing <i>Salmonella</i> Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma.

Ebelt Nancy D ND Zuniga Edith E Passi Kevin B KB Sobocinski Lukas J LJ Manuel Edwin R ER

Molecular cancer therapeutics 20191106 2

In pancreatic ductal adenocarcinoma (PDAC), the extracellular matrix (ECM) surrounding cancer cells forms a barrier that often limits the ability of chemotherapeutic drugs and cytotoxic immune subsets to penetrate and eliminate tumors. The dense stromal matrix protecting cancer cells, also known as desmoplasia, results from the overproduction of major ECM components such as collagens and hyaluronic acid (HA). Although candidate drugs targeting ECM components have shown promise in increasing pene ...[more]

PMID: 31694889

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Project description:BackgroundPancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive desmoplastic stromal response. Fibroblast activation protein-α (FAP) is best known for its presence in stromal cancer-associated fibroblasts (CAFs). Our aim was to assess whether FAP expression was associated with the prognosis of patients with PDAC and to investigate how FAP expressing CAFs contribute to the progression of PDAC.MethodsFAP expression was immunohistochemically assessed in 48 PDAC specimens. We also generated a fibroblastic cell line stably expressing FAP, and examined the effect of FAP-expressing fibroblasts on invasiveness and the cell cycle in MiaPaCa-2 cells (a pancreatic cancer cell line).ResultsStromal FAP expression was detected in 98% (47/48) of the specimens of PDAC, with the intensity being weak in 16, moderate in 19, and strong in 12 specimens, but was not detected in the 3 control noncancerous pancreatic specimens. Patients with moderate or strong FAP expression had significantly lower cumulative survival rates than those with negative or weak FAP expression (mean survival time; 352 vs. 497 days, P = 0.006). Multivariate analysis identified moderate to strong expression of FAP as one of the factors associated with the prognosis in patients with PDAC. The intensity of stromal FAP expression was also positively correlated to the histological differentiation of PDAC (P < 0.05). FAP-expressing fibroblasts promoted the invasiveness of MiaPaCa-2 cells more intensively than fibroblasts not expressing FAP. Coculture with FAP-expressing fibroblasts significantly activated cell cycle shift in MiaPaCa-2 cells compared to coculture with fibroblasts not expressing FAP. Furthermore, coculture with FAP expressing fibroblasts inactivated retinoblastoma (Rb) protein, an inhibitor of cell cycle progression, in MiaPaCa-2 cells by promoting phosphorylation of Rb.ConclusionsThe present in vitro results and the association of FAP expression with clinical outcomes provide us with a better understanding of the effect of FAP-expressing CAFs on the progression of PDAC.

Dataset Information

Hyaluronidase-Expressing Salmonella Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma.

Publications

Hyaluronidase-Expressing <i>Salmonella</i> Effectively Targets Tumor-Associated Hyaluronic Acid in Pancreatic Ductal Adenocarcinoma.

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