Targeting the Tumor Microenvironment for Pancreatic Ductal Adenocarcinoma Therapy

Yi-Fan Zhang; Shu-Heng Jiang; Li-Peng Hu; Pei-Qi Huang; Xu Wang; Jun Li; Xue-Li Zhang; Hui-Zhen Nie; Zhi-Gang Zhang


Chin Clin Oncol. 2019;8(2) 

In This Article

Neural Invasion and Neuroendocrinology

Neural invasion may depend on specific cancer cells and their interaction with the neural stroma.[52] Neural invasion is a pathohistological hallmark of PDAC, and the observed incidence in PDAC is as high as 100%.[53,54] The nerves that infiltrate the pancreatic tumor tissue interact with the TME to play an important role in carcinogenesis, tumor development and metastasis.

The complex tumor microenvironment has numerous factors that affect tumor development, and neurotransmitters must be included. For normal pancreatic beta-cells, dopamine increases proliferation, decreases apoptosis by extending intracellular cAMP content and prevents beta-cell dedifferentiation.[55] However, in tumor tissue, dopamine receptors are activated and inhibit cancer cell growth and migration at both the cell level and tumor level in mice with xenografts.[56] Some research reports that nitric oxide (NO) suppresses pancreatic cell apoptosis, and the overproduction of NO reduces insulin secretion.[57,58] Pancreatic cancer cells express a high level of inducible NO synthase due to the overproduction of NO, and a high level of NO is significantly associated with poor survival.[59] NO may be a therapeutic target and predictor of prognosis in the early stages.

Serotonin (5-HT) is a neurotransmitter in the central nervous system, and it also acts as a hormone in the peripheral region. 5-HT cannot cross the blood-brain barrier so 95% of 5-HT is directly produced in the periphery. In healthy bodies, 5-HT regulates pancreatic beta-cell autocrine function, promotes gluconeogenesis, suppresses glucose uptake, regulates adipose and affects other organs.[60] In PDAC, 5-HT uptake promoted activation of the small GTPase Ras-related C3 botulinum toxin substrate 1 (Rac1), which is required for the transdifferentiation of acinar cells into acinar-to-ductal metaplasia (ADM), a key determinant in PDAC development.[61] The level of 5-HT increases in PDAC tissue, and 5-HT promotes proliferation, prevents cell apoptosis, increases levels of metabolic enzymes involved in glycolysis, and increases participation in the phosphate pentose pathway and hexosamine biosynthesis pathway, activates PI3K-Akt-mTOR signaling and affects the Warburg effect by increasing protein levels of MYC and HIF1A.[62] Gamma-aminobutyric acid (GABA) is a major neurotransmitter in the central nervous system and is widely distributed in the peripheral region; GABRP, a receptor of GABA, has been reported to have a close relationship with PDAC. GABRP interacts with macrophages. GABRP induces macrophages into PDAC tissue, and the deletion of macrophages mechanistically abrogates the oncogenic function of GABRP as GABRP interacts with KCNN4 to induce Ca2+entry, which leads to activation of the NF-κB signaling pathway and ultimately facilitates macrophage infiltration by inducing CXCL5 and CCL20 expression.[63]

Hormones adjust cell metabolism, growth, and differentiation, and these physiological process changes are hallmarks of cancer. Chronic psychological stress may promote tumor development, and norepinephrine (NE) is the main hormone in the response to stress. Researchers have reported that NE may promote the biological behavior of malignant PDAC through the Notch-1 pathway.[64] Angiotensin has not been reported to directly affect PDAC cells; however, the expression of angiotensin-converting enzyme 2 (ACE2) decreases in PDAC tissue, and a reduction of ACE2 expression promotes pancreatic cancer cell proliferation.[65] Furthermore, chronic systemic angiotensin inhibitor use in primary PDAC is associated with longer overall survival independent of chemotherapy due to the reduction of potentially malignant cancer cells and stimulation of the immune system.[66] To break PDAC chemoresistance, research has attempted to use melatonin to inhibit the activation of NF-κB and increase melatonin expression by sorafenib to block the PDGFR-β/STAT3 pathway because the melatonin receptor mediates STAT3.[67,68]

P2RY2 is a purinergic receptor activated by ATP and belongs to the G-protein coupled receptor family. Investigations have revealed that inhibiting P2RY2 impaired cell growth and delayed tumor development because of its roles in reprogramming PDAC metabolism.[69]

Insulin is an important hormone secreted by the pancreas. Increases in insulin and glucose concentration promote fibrosing response and cell proliferation in type 2 diabetes, which may be associated with PDAC.[70] Apart from regulating glycometabolism, insulin with the insulin-like growth factor (IGF) family also promotes cell proliferation. Insulin/IGF signaling (IIS) drives cell proliferation via the Yorkie/YAP pathway, and YAP can be stimulated by insulin receptor and G protein-coupled receptor (GPCR) crosstalk through PI3K and PKD in PDAC.[71,72] In addition to directly affecting PDAC cells, insulin also affects downstream factors, such as hormone-sensitive lipase, which regulates pancreatic cancer development.[73]

Hormones and immunocytes can affect tumor development together. Pancreatic cancer cells secrete high levels of adrenomedullin (ADM), and CD11b+ myelomonocytic cells express all AMD receptor components, through which myelomonocytic cells enhance migration and invasion activities through the MAPK, PI3K/Akt and eNOS signaling pathways, as well as the expression and activity of MMP-2. Furthermore, AMD increases the expression of VCAM-1 and ICAM-1 to promote the adhesion and trans-endothelial migration of myelomonocytic cells in endothelial cells, and as we all know, myelomonocytic cells are related to tumor development.[74]