Functional Property and Regulatory Mechanism of Macrophages in Complementary and Alternative Medicine: From Bench to Clinic.

Complementary and alternative medicine (CAM) includes a wide range of treatments that are gaining acceptance among the public. It is increasingly being recognized as a viable option for treating various diseases with minimal side effects. Common avenues of this therapy include herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy, and homeopathy etc. Macrophages are highly heterogeneous cells that play multiple regulatory roles. Practices such as herbal medicine, acupuncture, physical exercise, aromatherapy and dietary therapy exert curative effects by modulating the polarization status and the secretory phenotype of macrophages directly. Furthermore, herbal medicine, acupuncture, and physical exercise influence the crosstalk between macrophages and other types of cells, including cancer cells and T cells. Mechanistically, herbal medicine and acupuncture produce curative effects in diverse diseases, including inflammatory diseases and tumors, mainly by influencing the phosphorylation of signaling proteins in macrophages. Therefore, targeting macrophages offers theoretical support for advancing the scientific understanding of this therapy and aids in identifying potential therapeutic options. Hence, in this review, we systematically summarize the different regulations of macrophages in herbal medicine, acupuncture, physical exercise, aromatherapy, dietary therapy and homeopathy, and further highlight the therapeutic potential of targeting macrophages in complementary and alternative medicine.

Lichen planus pemphigoides induced by anti-PD-1 antibody: A case only involved in oral mucosa with excellent topical treatment efficiency.

Lichen planus pemphigoides (LPP) is a rare autoimmune subepidermal disease that can occur in patients receiving immune checkpoint inhibitors. Its clinical manifestations are combined with the characteristics of lichen planus with bullous pemphigoid that can occur on either skin or oral mucosa. It should be noted that oral LPP is very rare. Here, we report a novel case of oral LPP induced by an anti-PD-1 agent. The patient presented with typical clinical features in oral mucosa, and the diagnosis was based on histopathology and immunological studies. Given that the patient was receiving an anti-PD-1 agent, topical therapy was chosen, and a nice therapeutic effect was obtained. No significant recurrence was observed after a 2-year follow-up. A good and stable therapeutic effect achieved by rapid and local symptomatic medication suggests that accurate and sensitive diagnosis is necessary.

Plunging Ranula Presenting as a Giant Anterior Cervical Cystic Mass: A Case Report and Literature Review.

Plunging ranula, a subtype of ranula, commonly presents as a submandibular or submental cystic mass without oral counterpart, and its clinical management remains challenging. Herein, the authors report an extremely rare case of 30-year-old female patient with plunging ranula involving the root of the left anterior neck.

Significant efficacy of short-course, low-concentration betamethasone mouthwash therapy for severe erosive oral lichen planus: a randomized controlled trial.

OBJECTIVES: To evaluate the short-term efficacy of low-concentration betamethasone mouthwash for severe erosive oral lichen planus (EOLP). MATERIALS AND METHOD: In this randomized, investigator-blind, positive-controlled trial, OLP patients with erosive lesions received betamethasone mouthwash (0.137 mg/mL) or dexamethasone mouthwash (0.181 mg/mL) three times daily for 2 or 4 weeks and were followed up for 3 months to observe recurrence. The primary outcome was the week-2 reduction in erosive area. RESULTS: Fifty-seven participants were randomized to betamethasone (n = 29) and dexamethasone (n = 28). At week 2, participants using betamethasone (n = 28) experienced a greater reduction in erosive area than gargling with dexamethasone (n = 26). Similarly, secondary outcomes, including the healing proportion of erosions, reduced pain level, reduction in atrophic area, Thongprasom score, and recurrence interval, showed the superiority of betamethasone. At week 4, betamethasone (n = 7) was not superior to dexamethasone (n = 15) in further reducing lesional area and pain level. No serious adverse events were documented. CONCLUSIONS: The 0.137 mg/mL compound betamethasone mouthwash exhibited significant efficacy in rapidly enhancing erosion healing within 2 weeks and extending the recurrence interval with a good safety profile. CLINICAL RELEVANCE: This study proved the significant efficacy of short-course 0.137 mg/mL betamethasone mouthwash therapy for treating erosion and pain, providing a novel topical agent for patients with severe EOLP. TRIAL REGISTRATION: This study was prospectively registered at the International Clinical Trials Registry Platform ( ChiCTR1800016507 ) on 5 June 2018.

Down-regulation of DNA key protein-FEN1 inhibits OSCC growth by affecting immunosuppressive phenotypes via IFN-γ/JAK/STAT-1.

Oral squamous cell carcinoma (OSCC) escape from the immune system is mediated through several immunosuppressive phenotypes that are critical to the initiation and progression of tumors. As a hallmark of cancer, DNA damage repair is closely related to changes in the immunophenotypes of tumor cells. Although flap endonuclease-1 (FEN1), a pivotal DNA-related enzyme is involved in DNA base excision repair to maintain the stability of the cell genome, the correlation between FEN1 and tumor immunity has been unexplored. In the current study, by analyzing the clinicopathological characteristics of FEN1, we demonstrated that FEN1 overexpressed and that an inhibitory immune microenvironment was established in OSCC. In addition, we found that downregulating FEN1 inhibited the growth of OSCC tumors. In vitro studies provided evidence that FEN1 knockdown inhibited the biological behaviors of OSCC and caused DNA damage. Performing multiplex immunohistochemistry (mIHC), we directly observed that the acquisition of critical immunosuppressive phenotypes was correlated with the expression of FEN1. More importantly, FEN1 directly or indirectly regulated two typical immunosuppressive phenotype-related proteins human leukocyte antigen (HLA-DR) and programmed death receptor ligand 1 (PD-L1), through the interferon-gamma (IFN-γ)/janus kinase (JAK)/signal transducer and activator transcription 1 (STAT1) pathway. Our study highlights a new perspective on FEN1 action for the first time, providing theoretical evidence that it may be a potential immunotherapy target for OSCC.

[Research Progress in the Application of Terahertz Spectroscopy and Imaging Technology in Stomatology].

Terahertz waves, the electromagnetic waves in the range of 0.1 to 10 THz, has the advantages of being damage-free, causing no ionizing radiation injury, and being capable of recognizing the fingerprint spectrum of molecular characteristics, thus holding encouraging prospects for wide applications in the field of biomedicine. Terahertz spectrum can be used to identify and characterize biological structures of different levels, from biomolecules such as proteins to cells and tissues, through the spectral signals and/or restored images of the samples. Herein, we summarized the current stomatogical application of and research progress in terahertz spectroscopy and imaging in dentistry, reported the latest research findings, strengths and limitations from three perspectives, tooth anatomical structure, the extent of caries progression, and oral soft tissue, and suggested possible directions for future exploration.

Ionizing radiation-induced "zombie" carcinoma-associated fibroblasts with suppressed pro-radioresistance on OSCC cells.

OBJECTIVES: This study was to investigate the effect of ionizing radiation (IR) on oral carcinoma-associated fibroblasts (CAFs) and to further explore subsequent effects of IR-induced "zombie" CAFs on oral squamous cell carcinoma (OSCC) cells. MATERIALS AND METHODS: Three primary CAFs and one primary normal-associated fibroblasts (NAFs) were separated from human OSCC and normal oral mucosa tissues, identified by immunocytochemistry. Cells were exposed to IR by X-ray irradiator under different doses. The DNA damage, proliferation, and migration of irradiated CAFs were, respectively, detected by immunofluorescence and wound healing assay, while senescence was detected by ß-galactosidase staining. Finally, the effect of irradiated CAFs on biological behavior and radioresistance of Cal-27 cells were determined via assays mentioned above. RESULTS: Oral CAFs were sensitive to IR with DNA damage increasing and proliferation decreasing. 18 Gy IR could not kill oral CAFs but induce them to "zombies," with arrested proliferation, increased senescence, and reduced migration. "Zombie" CAFs (zCAFs) could enhance proliferation, migration, and invasion of Cal-27 cells, and show suppressed pro-radioresistance by reducing DNA damage and facilitating survival. CONCLUSIONS: IR-induced zCAFs could continuously promote radioresistance of OSCC cells though being suppressed, suggesting the potential promoting effect on tumor relapse post-radiotherapy that needed further exploring.

Tailoring biomaterials and applications targeting tumor-associated macrophages in cancers.

Tumor-associated macrophages (TAMs) play a critical role in supporting tumor growth and metastasis, taming host immunosurveillance, and augmenting therapeutic resistance. As the current treatment paradigms for cancers are generally insufficient to exterminate cancer cells, anti-cancer therapeutic strategies targeting TAMs have been developed. Since TAMs are highly heterogeneous and the pro-tumoral functions are mediated by phenotypes with canonical surface markers, TAM-associated materials exert anti-tumor functions by either inhibiting polarization to the pro-tumoral phenotype or decreasing the abundance of TAMs. Furthermore, TAMs in association with the immunosuppressive tumor microenvironment (TME) and tumor immunity have been extensively exploited in mounting evidence, and could act as carriers or accessory cells of anti-tumor biomaterials. Recently, a variety of TAM-based materials with the capacity to target and eliminate cancer cells have been increasingly developed for basic research and clinical practice. As various TAM-based biomaterials, including antibodies, nanoparticles, RNAs, etc., have been shown to have potential anti-tumor effects reversing the TME, in this review, we systematically summarize the current studies to fully interpret the specific properties and various effects of TAM-related biomaterials, highlighting the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-cancer therapy.

TGF-ß signaling in the tumor metabolic microenvironment and targeted therapies.

Transforming growth factor-ß (TGF-ß) signaling has a paradoxical role in cancer progression, and it acts as a tumor suppressor in the early stages but a tumor promoter in the late stages of cancer. Once cancer cells are generated, TGF-ß signaling is responsible for the orchestration of the immunosuppressive tumor microenvironment (TME) and supports cancer growth, invasion, metastasis, recurrence, and therapy resistance. These progressive behaviors are driven by an "engine" of the metabolic reprogramming in cancer. Recent studies have revealed that TGF-ß signaling regulates cancer metabolic reprogramming and is a metabolic driver in the tumor metabolic microenvironment (TMME). Intriguingly, TGF-ß ligands act as an "endocrine" cytokine and influence host metabolism. Therefore, having insight into the role of TGF-ß signaling in the TMME is instrumental for acknowledging its wide range of effects and designing new cancer treatment strategies. Herein, we try to illustrate the concise definition of TMME based on the published literature. Then, we review the metabolic reprogramming in the TMME and elaborate on the contribution of TGF-ß to metabolic rewiring at the cellular (intracellular), tissular (intercellular), and organismal (cancer-host) levels. Furthermore, we propose three potential applications of targeting TGF-ß-dependent mechanism reprogramming, paving the way for TGF-ß-related antitumor therapy from the perspective of metabolism.

Functional Properties of Cancer Epithelium and Stroma-Derived Exosomes in Head and Neck Squamous Cell Carcinoma.

Stroma-cancer cell crosstalk involves a complex signaling network that contributes to tumor progression, including carcinogenesis, angiogenesis, migration, invasion, and therapy resistance in cancers. Exosomes, as extracellular membranous nanovesicles released by almost all types of cells, including tumor cells and stromal cells, play a critical role in signal delivery and material communication, in which the characteristics of their parent cells are reflected. The tumor or stroma-derived exosomes mediate cell-cell communication in the tumor microenvironment by transporting DNA, RNA, proteins, lipids, and metabolites. Recent studies on head and neck squamous cell carcinoma (HNSCC) have demonstrated that tumor-derived exosomes support various tumor biological behaviors, whereas the functional roles of stroma-derived exosomes remain largely unknown. Although these exosomes are emerging as promising targets in early diagnosis, prognostic prediction, and pharmaceutical carriers for antitumor therapy, there are still multiple hurdles to be overcome before they can be used in clinical applications. Herein, we systematically summarize the promotive roles of the epithelium and stroma-derived exosomes in HNSCC and highlight the potential clinical applications of exosomes in the treatment of HNSCC.

Therapeutic Approaches Targeting Proteins in Tumor-Associated Macrophages and Their Applications in Cancers.

Tumor-associated macrophages (TAMs) promote tumor proliferation, invasion, angiogenesis, stemness, therapeutic resistance, and immune tolerance in a protein-dependent manner. Therefore, the traditional target paradigms are often insufficient to exterminate tumor cells. These pro-tumoral functions are mediated by the subsets of macrophages that exhibit canonical protein markers, while simultaneously having unique transcriptional features, which makes the proteins expressed on TAMs promising targets during anti-tumor therapy. Herein, TAM-associated protein-dependent target strategies were developed with the aim of either reducing the numbers of TAMs or inhibiting the pro-tumoral functions of TAMs. Furthermore, the recent advances in TAMs associated with tumor metabolism and immunity were extensively exploited to repolarize these TAMs to become anti-tumor elements and reverse the immunosuppressive tumor microenvironment. In this review, we systematically summarize these current studies to fully illustrate the TAM-associated protein targets and their inhibitors, and we highlight the potential clinical applications of targeting the crosstalk among TAMs, tumor cells, and immune cells in anti-tumor therapy.

TGF-ßRII regulates glucose metabolism in oral cancer-associated fibroblasts via promoting PKM2 nuclear translocation.

Cancer-associated fibroblasts (CAFs) are highly heterogeneous and differentiated stromal cells that promote tumor progression via remodeling of extracellular matrix, maintenance of stemness, angiogenesis, and modulation of tumor metabolism. Aerobic glycolysis is characterized by an increased uptake of glucose for conversion into lactate under sufficient oxygen conditions, and this metabolic process occurs at the site of energy exchange between CAFs and cancer cells. As a hallmark of cancer, metabolic reprogramming of CAFs is defined as reverse Warburg effect (RWE), characterized by increased lactate, glutamine, and pyruvate, etc. derived from aerobic glycolysis. Given that the TGF-ß signal cascade plays a critical role in RWE mainly through metabolic reprogramming related proteins including pyruvate kinase muscle isozyme 2 (PKM2), however, the role of nuclear PKM2 in modifying glycolysis remains largely unknown. In this study, using a series of in vitro and in vivo experiments, we provide evidence that TGF-ßRII overexpression suppresses glucose metabolism in CAFs by attenuating PKM2 nuclear translocation, thereby inhibiting oral cancer tumor growth. This study highlights a novel pathway that explains the role of TGF-ßRII in CAFs glucose metabolism and suggests that targeting TGF-ßRII in CAFs might represent a therapeutic approach for oral cancer.

Fundamental and Clinical Applications of Materials Based on Cancer-Associated Fibroblasts in Cancers.

Cancer stromal cells play a role in promoting tumor relapse and therapeutic resistance. Therefore, the current treatment paradigms for cancers are usually insufficient to eradicate cancer cells, and anti-cancer therapeutic strategies targeting stromal cells have been developed. Cancer-associated fibroblasts (CAFs) are perpetually activated fibroblasts in the tumor stroma. CAFs are the most abundant and highly heterogeneous stromal cells, and they are critically involved in cancer occurrence and progression. These effects are due to their various roles in the remodeling of the extracellular matrix, maintenance of cancer stemness, modulation of tumor metabolism, and promotion of therapy resistance. Recently, biomaterials and nanomaterials based on CAFs have been increasingly developed to perform gene or protein expression analysis, three-dimensional (3D) co-cultivation, and targeted drug delivery in cancer treatment. In this review, we systematically summarize the current research to fully understand the relevant materials and their functional diversity in CAFs, and we highlight the potential clinical applications of CAFs-oriented biomaterials and nanomaterials in anti-cancer therapy.

Cancer-Associated Fibroblasts Facilitate Squamous Cell Carcinoma Lung Metastasis in Mice by Providing TGFß-Mediated Cancer Stem Cell Niche.

Cancer-associated fibroblasts (CAFs) have been shown to enhance squamous cell carcinoma (SCC) growth, but it is unclear whether they promote SCC lung metastasis. We generated CAFs from K15.KrasG12D.Smad4-/- mouse SCCs. RNA expression analyses demonstrated that CAFs had enriched transforming growth factor-beta (TGFß) signaling compared to normal tissue-associated fibroblasts (NAFs), therefore we assessed how TGFß-enriched CAFs impact SCC metastasis. We co-injected SCC cells with CAFs to the skin, tail vein, or the lung to mimic sequential steps of lung metastasis. CAFs increased SCC volume only in lung co-transplantations, characterized with increased proliferation and angiogenesis and decreased apoptosis compared to NAF co-transplanted SCCs. These CAF effects were attenuated by a clinically relevant TGFß receptor inhibitor, suggesting that CAFs facilitated TGFß-dependent SCC cell seeding and survival in the lung. CAFs also increased tumor volume when co-transplanted to the lung with limiting numbers of SCC cancer stem cells (CSCs). In vitro, CSC sphere formation and invasion were increased either with co-cultured CAFs or with CAF conditioned media (which contains the highest TGFß1 concentration) and these CAF effects were blocked by TGFß inhibition. Further, TGFß activation was higher in primary human oral SCCs with lung metastasis than SCCs without lung metastasis. Similarly, TGFß activation was detected in the lungs of mice with micrometastasis. Our data suggest that TGFß-enriched CAFs play a causal role in CSC seeding and expansion in the lung during SCC metastasis, providing a prognostic marker and therapeutic target for SCC lung metastasis.

Signaling pathways in cancer-associated fibroblasts and targeted therapy for cancer.

To flourish, cancers greatly depend on their surrounding tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in TME are critical for cancer occurrence and progression because of their versatile roles in extracellular matrix remodeling, maintenance of stemness, blood vessel formation, modulation of tumor metabolism, immune response, and promotion of cancer cell proliferation, migration, invasion, and therapeutic resistance. CAFs are highly heterogeneous stromal cells and their crosstalk with cancer cells is mediated by a complex and intricate signaling network consisting of transforming growth factor-beta, phosphoinositide 3-kinase/AKT/mammalian target of rapamycin, mitogen-activated protein kinase, Wnt, Janus kinase/signal transducers and activators of transcription, epidermal growth factor receptor, Hippo, and nuclear factor kappa-light-chain-enhancer of activated B cells, etc., signaling pathways. These signals in CAFs exhibit their own special characteristics during the cancer progression and have the potential to be targeted for anticancer therapy. Therefore, a comprehensive understanding of these signaling cascades in interactions between cancer cells and CAFs is necessary to fully realize the pivotal roles of CAFs in cancers. Herein, in this review, we will summarize the enormous amounts of findings on the signals mediating crosstalk of CAFs with cancer cells and its related targets or trials. Further, we hypothesize three potential targeting strategies, including, namely, epithelial-mesenchymal common targets, sequential target perturbation, and crosstalk-directed signaling targets, paving the way for CAF-directed or host cell-directed antitumor therapy.

Glycolysis reprogramming in cancer-associated fibroblasts promotes the growth of oral cancer through the lncRNA H19/miR-675-5p/PFKFB3 signaling pathway.

As an important component of the tumor microenvironment, cancer-associated fibroblasts (CAFs) secrete energy metabolites to supply energy for tumor progression. Abnormal regulation of long noncoding RNAs (lncRNAs) is thought to contribute to glucose metabolism, but the role of lncRNAs in glycolysis in oral CAFs has not been systematically examined. In the present study, by using RNA sequencing and bioinformatics analysis, we analyzed the lncRNA/mRNA profiles of normal fibroblasts (NFs) derived from normal tissues and CAFs derived from patients with oral squamous cell carcinoma (OSCC). LncRNA H19 was identified as a key lncRNA in oral CAFs and was synchronously upregulated in both oral cancer cell lines and CAFs. Using small interfering RNA (siRNA) strategies, we determined that lncRNA H19 knockdown affected proliferation, migration, and glycolysis in oral CAFs. We found that knockdown of lncRNA H19 by siRNA suppressed the MAPK signaling pathway, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) and miR-675-5p. Furthermore, the lncRNA H19/miR-675-5p/PFKFB3 axis was involved in promoting the glycolysis pathway in oral CAFs, as demonstrated by a luciferase reporter system assay and treatment with a miRNA-specific inhibitor. Our study presents a new way to understand glucose metabolism in oral CAFs, theoretically providing a novel biomarker for OSCC molecular diagnosis and a new target for antitumor therapy.

The hypothesis of tumor-associated macrophages mediating semi-phagocytosis of cancer cells in distant metastasis.

Tweetable abstract Tumor-associated macrophages might promote the distant metastasis of tumor cells by semi-phagocytosis. The authors propose that this newly discovered process occurs in tumor-associated macrophages and may lead to a novel approach for blocking cancer metastasis.