TAM Infiltration Differences in “Tumor-First” and “ZHENG-First” Models and the Underlying Inflammatory Molecular Mechanism in Pancreatic Cancer

Abstract

Background: Syndrome (ZHENG in Chinese) in traditional Chinese medicine (TCM) refers to the intrinsic characteristics of a pathological process at a certain stage; these characteristics are influenced by internal and external environments and reveal the nature of a disease. Proper syndrome differentiation is the basic principle that guides clinical treatment. Objective: To have a good understanding of tumor progression and the different mechanisms related to ZHENG that have occurred before and after tumor development and to explore the valid evaluation criteria of different pancreatic cancer syndromes to improve the guiding role of TCM syndrome differentiation in pancreatic cancer treatment. Methods: In this study, we established mouse subcutaneous pancreatic cancer models, namely, Con (control), Pi-Xu (Spleen-Deficiency), Shi-Re (Dampness-Heat), and Xue-Yu (Blood-Stasis). Then, for the first time, we compared the different effects of “ZHENG-first” (referring to a different disease status that occurred before tumor occurrence) and “Tumor-first” (referring to the change in the tumor microenvironment and the resulting changes in the state of the body) conditions on tumor progression and evaluated the associated molecular mechanisms. Results: We found that tumor growth in the “ZHENG-first” and “Tumor-first” conditions was different. In the “Tumor-first” model, the tumor growth in the Pi-Xu group was faster than that in the other groups. However, in the “ZHENG-first” model, the tumor growth trend was most obvious in the Shi-Re group. There was a difference in tumor-associated macrophage infiltration between the 2 models. The expression levels of the inflammatory cytokines IL-6, IL-10, and P-STAT3 were also differentially altered. Conclusion: The emergence of ZHENG conditions before or after tumor occurrence had different impacts on pancreatic cancer development, and these impacts may be related to differences in tumor-associated macrophage infiltration and the involved inflammatory cytokines IL-6, IL-10, and P-STAT3. The study results uncovered the molecular basis of syndrome differentiation in pancreatic cancer progression, which might provide more specific guidance for TCM treatment of pancreatic cancer.

A Mouse Model of Damp-Heat Syndrome in Traditional Chinese Medicine and Its Impact on Pancreatic Tumor Growth

“…First, the appearance and behavior of the mice with damp-heat syndrome described above were similarly seen in pancreatic tumor-bearing mice with damp-heat syndrome ( Figure 5A , upper panel). Consistent with the findings of our previous study ( 10 ), damp-heat syndrome significantly promoted the growth of pancreatic tumors ( Figures 5B–D ); this was further evidenced by Ki67 staining ( Figure 5F ). In addition, tumor-bearing mice with damp-heat syndrome seemed to have a more rapid body weight gain than the mice of other groups ( Figure 5E ).…”

“…To induce damp-heat syndrome, both a previous method ( 10 ) and an optimized new method were adopted. The mice in the old method group received honey water (200 g/L), a standard chow diet, and intragastric administrations of 0.3 ml dissolved lard and 0.2 ml liquor for 7 days.…”

Elucidation of the Reinforcing Spleen Effect of Jujube Fruits Based on Metabolomics and Intestinal Flora Analysis

“…Metabolomics is a holistic approach to the analysis of endogenous low-molecular-weight metabolites in various biological samples, which allows simultaneous monitoring of multiple metabolic pathways and reasonable speculation on the regulation of these pathways based on metabolite expression (up- or down- regulation) data ( Zhang et al., 2020a ). This concept is consistent with the integral and systematic characteristics of TCM theory, which focuses on harmonizing the overall internal and external environment of the human body, maintaining the balance of physiological functions of the body, and then improving its immunity and resistance ( Li et al., 2015 ; Wang et al., 2018 ). Therefore, metabolomics has been widely used in efficacy evaluation and clarification of possible mechanisms of TCM ( Yan et al., 2020 ; Yang and He, 2020 ).…”

Kaempferol induces ROS-dependent apoptosis in pancreatic cancer cells via TGM2-mediated Akt/mTOR signaling

“…Immunohistochemistry (IHC) staining was performed as previously described [ 19 ]. In brief, the paraffin-embedded tumor sections were dewaxed in xylene and then rehydrated with a graded alcohol series.…”