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

Disclosures

Chin Clin Oncol. 2019;8(2) 

In This Article

Abstract and Introduction

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the most dangerous cancers, and the overall 5-year survival rate is only 8%. The microenvironment of PDAC, which promotes tumorigenesis, disease development and metastasis, consists of fibroblasts, immune cells, pancreatic stellate cells (PaSCs), adipocytes and extracellular matrix (ECM). Because the microenvironment is a part of the tumor, it is also an important target for PDAC treatment. Several therapeutic regimens targeting PDAC microenvironment factors or cells have been investigated, but the treatment effects were poor. More research on the physiological and pathological mechanisms and clinical treatment of PDAC is necessary.

Introduction

Pancreatic cancer is one of the most dangerous cancers, and it has a very low overall 5-year survival rate (8%) that has shown little improvement.[1] There are 10 types of major neoplasms of the pancreas, and invasive ductal adenocarcinoma is common.[2] Pancreatic ductal adenocarcinoma (PDAC) cells infiltrate into the tissue to make the tumor firm and metastasize to other organs.[3]

Solid tumor cancer cells exhibit self-sufficiency in growth signals, which results in unlimited cell proliferation, the ability to obtain nutrients, resistance to apoptosis, insensitivity to the growth inhibitory pathway, and the capacity to invade and metastasize.[4] PDAC has these characteristics as well. Through microscopy, PDAC cells were observed to have a close relationship with nerves, lymphatic spaces and small veins, indicating that PDAC is very likely to become a metastatic carcinoma. The tumor microenvironment (TME) of PDAC is highly immunosuppressive and has been associated with cell secretion disorders and interactions with nerves.[5–7] The majority of the PDAC tumor volume is filled by stroma/desmoplastic reaction, and the heterogeneous stroma consists of fibroblasts, myofibroblasts, immune cells, pancreatic stellate cells (PaSCs), extracellular matrix (ECM), and soluble proteins, such as cytokines, growth factors and blood vessels.[8,9] The interaction of the tumor cells with factors in TME suppresses the immune reaction of the body to escape immunocyte apoptosis. Due to the complex tumor microenvironment and high interstitial fluid pressure (IFP), PDAC has chemoresistance and radioresistance, which creates major challenges for therapy.[10] The interactions between components in TME and the tumor cells results in tumor development, metastasis and immune escape. In addition to poor therapy effects, there is no early detection test for PDAC, and many patients lack recognizable symptoms or signs of the disease. Therefore, patients are continuously considered to be at high-risk after being diagnosed with PDAC.

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