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

Fibroblasts

Desmoplasia is an important feature of the PDAC tumor microenvironment but can be an obstacle for therapeutic agents; fibroblasts are considered to be "murderers" that result in desmoplasia. Cancer cells expend a large amount of energy to recruit, proliferate and activate fibroblasts; then, as a reward, the activated fibroblasts deposit ECM and secrete numerous factors that affect tumor development[11] (Figure 1). An important origin of cancer-associated fibroblasts (CAFs) is from the Notch signaling pathway that activates PaSCs.[12]

Figure 1.

The relationship between PDAC cells, fibroblasts and the ECM. PDAC cells expend energy to recruit fibroblasts during its early development stage by secreting factors such as SHH, SDF-1, TGF-β1 and PDGF. Fibroblasts deposit into the ECM and promote tumor cell proliferation, invasion and metastasis by secreting PGDF and SDF-1. The dense ECM promotes PDAC development through stimulation of the integrin/FAK signaling pathway in PDAC cells and contact-mediated lymphocyte trapping. PDAC, pancreatic ductal adenocarcinoma; ECM, extracellular matrix.

Several types of fibroblasts are deposited in the ECM, which may explain the poor therapy results of targeting CAFs. Two major types of PDAC FAP+ fibroblasts exist: periglandular αSMAhigh myofibroblastic CAFs (myCAFs), which likely restrain tumor growth; and diffusely distributed αSMAlow interleukin-6 (IL-6)-positive inflammatory CAFs, which promote tumor growth by secreting ECM proteins and cytokines such as IL-6 and IL-11.[13,14] Based on the fibroblast subtype, inhibiting IL-6R to reduce STAT3 activation slows tumor development.[15] Although there are two types of CAFs and their functions seem to be opposed, CAFs were demonstrated to be a promoting tumor factor in the TME. The PDAC cell interactions with stromal fibroblasts increase hyaluronic acid production, causing an obvious increase in the migration of PDAC cells.[16] New research has reported that the Wnt-nonproducing subtype, a kind of PDAC cell, required Wnt from CAFs.[17]

CAFs stop CD8+ and CD4+ T cells, NK cells and Tregs to juxtatumoral compartments to exert normal physiological function.[18–20] CAFs secrete CXCL12 to keep CXCR4+ T cells away from tumors and secrete CCL5, CCL2 and CCL17 to recruit monocytes and Tregs, which results in immunosuppression.[21] Due to the presence of fibroblasts and other stellate cells, tumors have high intratumor IFP and matricellular tension (MCT),[22] both of which promote tumor progression, reduce vasculature to cut off therapeutic agents and induces tissue hypoxia.[23] Subsequently, through autophagy-mediated degradation and a reduction in protein synthesis in the PaSCs, hypoxia reduces the expression of lumican, an inhibitor of tumor progression that is located in the TME.[24]

During tumor metastasis, the fibroblasts, along with other cells, affect the microenvironment of the target organ. During the early stage of PDAC liver metastasis, metastasis-associated macrophages (MAMs), a kind of inflammatory monocyte, secrete granulin and activate resident hepatic stellate cells that turn into myofibroblasts, which secrete periostin to result in a fibrotic microenvironment that promotes metastatic tumor growth.[25] This finding may explain why myofibroblasts appear when metastases only comprise 6–7 cells in the cell population within a metastatic lesion.[26] Research has shown that PDAC cells that are treated with CAF-conditioned media have an increased risk of metastasis; the reason for this increase is the loss of metastasis suppressor 1.[27]

Since the elimination of desmoplasia has been indicated be harmful to patients, new research is more focused on ECM reprogramming to find new effective therapeutic agents. Malik et al. reported that CAFs remodel cell-derived extracellular matrices (CDMs) by altering the underlying substrate stiffness and inhibit tumor growth in an extracellular signal-regulated kinase 2 (EKR2)-dependent manner.[28] CAFs treated with physiological stiffness (~1.5 kPa) generate CDMs similar to normal fibroblasts, and the biomechanical manipulation generated on physiological stiffness CDMs leads to a decrease in the nuclear translocation of pERK1/2 in KRAS-mutated pancreatic cells.

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