Targeting Hypoxic Tumor Microenvironment in Pancreatic Cancer: An Emerging Innovative Concept

According to NCI, in 2021, there will be an estimated 60431 new cases of PC and an estimated 48220 people will die from it, placing PC as the 3 rd largest case of cancer related deaths in US. Severe hypoxic regions are hallmarks of PC with a median tissue partial oxygen pressure (pO 2 ) of 0-5.3mmHg (0-0.7%) compared to the adjacent normal pancreas pO 2 at 24.3-92.7mmHg (3.2-12.3%) The presence of hypoxic areas within PC spur tumor progression and exacerbates poor clinical outcome in PC patients. Hypoxia is considered as one of the independent prognostic factors for PC [9]. PC induces a hypoxic tumor environment that drives the production of HIF1 and stabilizes it [9,10]. Pilli et al. [11] have made the novel observation that protein S (PS), a natural human plasma protein that participates in coagulation control and has multiple receptor-mediated effects [12] has activity on in vitro models of pancreatic cancer (PC) cells. PS is a 75-kDa vitamin K-dependent glycoprotein synthesized by hepatocytes, endothelial cells, and megakaryocytes and is involved in many physiological processes; hemostasis, apoptosis, and inflammation [13]. The plasma concentration of PS is reportedly reduced during the progression of PDAC [14]. Pilli et al. [11] also demonstrated that expressing PS in PC cell lines reduces their aggressiveness. The investigators made a compelling case to supplement PS to control PC. Pilli et al. [15] have previously shown that PS deficiency augments the hypoxic niche by stabilizing HIF1 and elevates thrombotic risk