@article{e4710ebf8a4f442ba0553f6b8ffd26a3,
title = "Hypoxia: Friend or Foe for drug delivery in Pancreatic Cancer",
abstract = "Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal solid tumors with an overall five-year survival rate of that has only just reached 10%. The tumor microenvironment of PDAC is characterized by desmoplasia, which consist of dense stroma of fibroblasts and inflammatory cells, resulting in a hypoxic environment due to limited oxygen diffusion through the tumor. Hypoxia contributes to the aggressive tumor biology by promoting tumor progression, malignancy, and promoting resistance to conventional and targeted therapeutic agents. In depth research in the area has identified that hypoxia modulates the tumor biology through hypoxia inducible factors (HIFs), which not only are the key determinant of pancreatic malignancy but also an important target for therapy. In this review, we summarize the recent advances in understanding hypoxia driven phenotypes, which are responsible for the highly aggressive and metastatic characteristics of pancreatic cancer, and how hypoxia can be exploited as a target for drug delivery.",
author = "Shah, {Vidhi M.} and Sheppard, {Brett C.} and Sears, {Rosalie C.} and Alani, {Adam WG}",
note = "Funding Information: V.M.S is supported by grant support from the Brenden-Colson Center for Pancreatic Care at OHSU . R.C.S acknowledges grant support from the NIH (1U01 CA224012, U2C CA233280, U54 CA209988, R01 CA196228, and R01 CA186241) and the Brenden-Colson Center for Pancreatic Care at OHSU . A.W.G is supported by grant support from NIH (1R15 CA227754, 1R37 CA234006). Funding Information: Metastasis is one of the main reasons behind the poor prognosis of PDAC. Hypoxia plays a major role in causing the metastatic phenotype by induction of the metastatic cascade: cancer cell invasion, including epithelial to mesenchymal transition (EMT) and invasive migration through the remodeled extracellular matrix, survival in blood, extravasation, colonization and finally growth of micrometastatic to macrometastatic disease [24]. To acquire properties of migration and invasion, the pancreatic cancer cells undergo a cellular program where they exchange their epithelial characteristics, such as apical-basal polarity and cell-cell adhesion, for mesenchymal traits via a cellular program known as EMT [25]. Following induction of EMT, the mesenchymal phenotype not only has enhanced migratory capacity, and invasiveness but also increased resistance to apoptosis and elevated production of extracellular matrix (ECM) components [26]. EMT increases the survival of cancer cells in blood and metastatic sites by induction of stem-cell like features and creating ECM tracks that other cancer cells can exploit [ 27?29]. Several studies have revealed that hypoxia induces epithelial plasticity and migratory phenotypes through direct and indirect regulation of hedgehog, nuclear factor kappa light chain enhancer of activated B cells and reactive oxidative species [ 30?32]. Tumor hypoxia has been correlated well with metastatic burden in both orthotopic xenografts of human pancreatic cell lines and patient derived xenografts [33,34]. Moreover, only a small portion of tumor cells have cancer stem cell (CSCs) features with the enhanced tumor initiating potential due to their self-renewal property and ability to differentiate to multiple cell types. Accumulating evidence has shown that hypoxia selects for CSC phenotypes and supports their generation and maintenance through regulation of HIF-dependent genes such as c-MYC, NANOG, and SOX2 [35,36]. Recently, it was shown that sustained and intermittent hypoxia induces CSC markers, and drives EMT in both CSC-like cells and CSCs in PDAC [32]. The cells with high CSC-like phenotype showed higher migratory capacity under hypoxia compared to cells with low CSC-like phenotype. Whereas, CSC-high cells displayed migratory capacity in normoxia due to expression of EMT markers like high vimentin, which gets augmented in hypoxia compared to CSC-low cells that are slowly transformed to mesenchymal phenotype when exposed to hypoxia [32]. Therefore, hypoxia induced cellular pathways which trigger migratory, invasiveness and CSC phenotypes contribute to the metastatic potential of PDAC.V.M.S is supported by grant support from the Brenden-Colson Center for Pancreatic Care at OHSU. R.C.S acknowledges grant support from the NIH (1U01 CA224012, U2C CA233280, U54 CA209988, R01 CA196228, and R01 CA186241) and the Brenden-Colson Center for Pancreatic Care at OHSU. A.W.G is supported by grant support from NIH (1R15 CA227754, 1R37 CA234006). Publisher Copyright: {\textcopyright} 2020 Elsevier B.V.",
year = "2020",
month = nov,
day = "1",
doi = "10.1016/j.canlet.2020.07.041",
language = "English (US)",
volume = "492",
pages = "63--70",
journal = "Cancer Letters",
issn = "0304-3835",
publisher = "Elsevier Ireland Ltd",
}