AcSDKP linked lipid profile and metabolic disturbances to induce PDAC
Metabolic reprogramming is one of the essential hallmarks of cancer through increase oncogenic signaling pathways and directly enhances nutrient acquisition to promote lipids, proteins, and nucleic acid assimilation [15]. The net result of this process affects cancer cell growth and proliferation. Pancreatic ductal adenocarcinoma (PDAC) is a kind of tumor with hypovascularization to induce oxygen and nutrient delivery to the tumor. This tumor enhances PDAC aggressiveness during metabolic reprogramming. We hypothesized that AcSDKP might enhance pancreatic cancer associated with a metabolic imbalance in particular related to lipid and glucose metabolism. Moreover, it is suggested that AcSDKP activity accelerates pancreatic cancer progression through involving in metabolic reprogramming and enhancing neoangiogenesis within the tumor site.
Here in our study, we found that the level of fasting blood glucose tended to increase in pancreatic cancer patients. Furthermore, we also found that the level of triglyceride significantly increased in our samples. In line with the previous finding, in cancer development, oncogenic ras stimulates both glucose uptake via glucose transporter-1 (GLUT-1) and utilization of glucose by anabolic pathways. Linear to by Daemen et al. study, in this PDAC clinical samples, the lipogenic subtype is more sensitive to the epithelial cell. In contrast, the glycolytic subtype is associated with mesenchymal cells to induce PDAC progression [16]. The significant feature of lipid and glucose profile of our subjects may stimulate the acceleration of tumor growth, facilitate cancer cell proliferation, metastasis, and aggressiveness [17]. In brief, it clarifies that the increase in obesity incidence is associated with the early stage of pancreatic cancer development. We speculate that increased AcSDKP expression induces liver lipid metabolic hormone activity and corroborate pancreatic injury. However, further investigation is required to improve our hypothesis of whether AcSDKP related fatty pancreatic and pancreatic fibrosis incidence caused by hypertriglyceridemia.
AcSDKP may accelerate PDAC through enhancing neovascularization, cancer cell proliferation, and pancreatic fibrosis
PDAC is a common cause of death from cancer in the world that ranks first in the mortality rate of all cancer [7, 18], characterized by hypovascular and highly desmoplastic cancer [19], and the incidence is increasing in age groups of > 50 years. Due to the late symptoms, resection is associated with improved survival rate, but this is only possible in approximately 10% of patients [20]. According to the cancer therapy perspective, the identification of an angiogenic network is crucial to develop an antiangiogenic therapy [21]. Even though some biomarkers or prognostic factors of PDAC has been explored, further investigation to trace a sensitive and specific tumor predictor that may be more valuable in diagnosis, improving prognosis, and to improve clinical outcome in PDAC patients is still required.
This study attempted to explore the role of AcSDKP in pancreatic cancer development. Here in our study, we proposed an additional novel biomarker for pancreatic cancer, AcSDKP, a cleavage tetrapeptide of Thymosin β4 as an inducer of cancer cell proliferation, migration, angiogenesis, and metastasis in many cancer cases. It has been established that growth and metastasis of pancreatic cancer depend on the activation of VEGF and other angiogenic factors. Signaling complex between cancer cells and adjacent endothelial cells is also suggested to promote aberrant vascularization/tumor angiogenesis [22]. Also, since pancreatic carcinoma shows active tumor neoangiogenesis, overexpression of a critical mediator of angiogenesis in pancreatic cancer (VEGF) becomes the target to develop anti-angiogenic therapies at present. Inhibition of neo-angiogenesis is a reliable and attractive target for tumor therapy. Indeed, the failure of the antiangiogenic agent is due to a single inhibitor that cannot inhibit the interconnection/network of angiogenesis signaling pathways [21]. Cross-inhibition of angiogenesis and apoptosis probably provide an extended benefit of combination cancer therapies consisting of antiangiogenics. Furthermore, establishing specific biomarker that plays a pivotal role in angiogenesis during PDAC development is essential to increase the patient survival rate.
Importantly, the study of Oh et al., 2010 has shown that TB4 paclitaxel treatment increases ROS production and triggers a significant increase in tumor density through hypoxia-inducible factor-1α (HIF-1α) stabilization in HeLa human cervical tumor cells. This linear finding also similar to a fundamental characteristic of PDAC with hypovascularization and resistance to antiangiogenic inhibitor in specific pathways. Moreover, a study claims that tolfenamic acid is a potential nonsteroidal anti-inflammatory drug (NSAID) to reduce angiogenesis through VEGF signaling pathway by degrading transcription factor Sp1, Sp3, and Sp4; and decrease tumor growth and metastasis [23]. On the other hand, another study suggests that the lower efficacy of VEGF-antiangiogenic drugs is due to the main focus of these treatments related to angiogenesis inhibition without combination to reduce tumor malignancy [24].
Previous studies have shown that Tβ4 is a potent inducer of angiogenesis in cancer development that presents in blood at nanomolar concentration, and relates to angiogenesis in particular for pancreatic cancer [7, 14]. Tβ4 also increases pancreatic cancer incidence (through inducing the elevation of proinflammatory cytokine production), increases the number of metastasis tumors, represses the anticancer immunity, controls tumor cell migration in angiogenesis, and controls tumor metastasis through HIF-1α [8, 25, 26]. Tβ4 is a small tetrapeptide that can be a novel target for the therapeutic approach of cancer, mainly tumor dormancy [25]. Besides, it also indicated accelerated severity and decreased the survival rate in multiple myeloma [10]. The solid tumor shows a switching process by changing the balance between angiogenesis inducer and countervailing inhibitor. Interestingly, the AcSDKP concentration is significantly increased within the intratumor blood of patients under the regulation of POP (prolyl oligopeptidase) [14, 27]. Indeed, AcSDKP has a unique function related to a particular pathologic condition. The amino-terminal site contains four amino acid that able to block inflammation and reduce fibrosis Transforming Growth Factor- β (TGFβ) signaling pathways [28–30], while another site of this polypeptide (amino terminus with 15 amino acids) promotes cell survival and inhibits apoptosis, angiogenesis, cell migration, and wound healing [30, 31].
Importantly, our study found that the level of AcSDKP significantly increased in pancreatic cancer patients, suggested that this pathological condition stimulates the increase of POP activity and angiogenesis to support tumor growth. However, the limitation of our study, we still cannot provide a complete molecular signaling network between AcSDKP and other biomarkers involved in pancreatic cancer. It is only hypothesized that the possible mechanism of AcSDKP activity during pancreatic cancer development by triggering the activation of pro-angiogenic molecules, cancer cell proliferation, and induced migration. Moreover, AcSDKP may be associated with other oncometabolomic molecules involved in nutrient supply, metabolic disturbances, and pancreatic fibrosis during cancer development. Therefore, further investigation should be addressed to the molecular pathways of AcSDKP in pancreatic cancer through EMT markers activity, and the downstream of pro-angiogenic inducer, in particular, VEGF as the potential targets for cancer therapy.
AcSDKP associated with betatrophin in pancreatic cancer
We also studied the correlation between AcSDKP to other parameters in pancreatic cancer progression. From our previous study, we found that the elevation of betatrophin concentration also correlates with pancreatic cancer incidence in patients with diabetes [32]. Here, our study showed that an attractive feature, whereas the level of AcSDKP is strongly associated with the serum level of betatrophin. This finding provides a novel molecular cross interaction between AcSDKP and betatrophin. Furthermore, the increase of AcSDKP concentration is in line with the elevation of liver injury markers (ALT, AST, and ALP). AcSDKP and betatrophin are produced in the liver, and both of these molecules suggested to regulate pancreatic cancer development that results in liver injury. Here in our study, the level of triglyceride and cholesterol also increases significantly in pancreatic cancer subjects. It is established that betatrophin regulates the degree of triglyceride by activating lipoprotein lipase (LPL) as the primary enzyme of triglycerides synthesis from lipid metabolism [33, 34]. In vivo study showed that knockout of betatrophin reveals about 70% reduction in plasma levels of [35]. Furthermore, it remains unknown whether pancreatic cancer patients stimulate the increase of hepatic AcSDKP expression to induce the elevation of betatrophin. In addition, our study also demonstrated that the serum levels of betatrophin were significantly correlated with AcSDKP levels.
In further analysis of this study, we found an exciting feature, whereas the serum levels of betatrophin can predict the pancreatic cancer progression by increase the odds-ratio of AcSDKP by quintile analysis. We speculate that AcSDKP corroborates pancreatic cancer development through cross molecular connection with betatrophin-LPL activity induce the increase of triglyceride levels. As a result, this pathological initiation process causes fatty pancreas as the pre-cancerous lesions during PDAC development. However, the underlying pattern of the molecular mechanism of this phenomenon is still unknown, and whether AcSDKP-betatrophin molecular interaction in pancreatic cancer associated with pancreatic fibrosis is not entirely elucidated.