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Immunofluorescent staining of CK19 and ASMA in primary cultures of fibroblasts derived from breast cancers (BCF) and adjacent areas of normal breast from surgical specimens (NTF). BCF 016, BCF 037 and BCF 044 are derived from different patients, whereas NTF are matched normal tissue fibroblasts pooled from patients 037 and 044. Breast cancer cell line MDA-MB-231 was used as a positive control for CK19. Hoechst (blue) staining shows the nuclei. Original magnification of 400x. Bars represent 20 μm.
Source publication
Cancer-associated fibroblasts and high mobility group box 1 (HMGB1) protein have been suggested to mediate cancer progression and chemotherapy resistance. The role of such fibroblasts in HMGB1 production in breast cancer is unclear. This study aimed to investigate the effects of cancer-associated fibroblasts on HMGB1 expression in breast cancer cel...
Context in source publication
Context 1
... and NTFs were characterized by their expression of the mesenchymal marker, ASMA, and absence of the epithelial marker, CK19. Immunocytochemical staining revealed that all cancer-associated and 'normal' breast fi- broblasts from six different patients were negative for CK19 compared with the positive control MDA-MB-231 breast cancer cells (Figure 1) and were positive for ASMA. Thus we confirmed that both BCFs and NTFs were mesenchymally-derived cells with no epithelial cell contamination. ...
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Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that aut...
Citations
... The protein structure of HMGB1 spans from the amino terminus to the carboxy terminus, encompassing an A box (residues 9-79), a B box (residues 95-163), and a receptorbinding motif (residues 186-215), which are exclusively composed of glutamic acid and aspartic acid. Crucially, HMGB1 contains two essential nuclear localization signals (NLS), specifically located at amino acids [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] and 179-185 (NLS2). These NLSs are responsible for the nuclear localization of HMGB1; moreover, they regulate its translocation between the nucleus and the cytoplasm upon post-translational modifications, such as phosphorylation and acetylation. ...
... This occurred through three mechanisms: 1) HMGB1 enhanced autophagy by activating ERK signaling, thus inhibiting mTOR activation and initiating the activity of the ULK1/ATG13/FIP200 complex; 2) HMGB1 inhibited apoptosis by restricting the BCL2/ BCL2 associated X (BCL2/BAX) pathway with TP53 involvement; and 3) HMGB1 activated the NF-kB pathway, thereby inducing the expression of P-glycoprotein (P-gp) and multidrug resistanceassociated protein (MRP) to expedite drug excretion (37). Similarly, Huang et al. confirmed the role of HMGB1 in multidrug resistance, including resistance to adriamycin, by regulating the formation of the BECN1/class III phosphatidylinositol 3-kinase (BECN1/PI3KC3) complex involved in autophagy in osteosarcoma (38,39). Furthermore, resistance to adriamycin caused by HMGB1 has also been found in breast cancer (40,41) and neuroblastoma (42). ...
High mobility group box 1 (HMGB1) is a nuclear DNA-binding protein with a dual role in cancer, acting as an oncogene and a tumor suppressor. This protein regulates nucleosomal structure, DNA damage repair, and genomic stability within the cell, while also playing a role in immune cell functions. This review comprehensively evaluates the biological and clinical significance of HMGB1 in cancer, including its involvement in cell death and survival, its potential as a therapeutic target and cancer biomarker, and as a prosurvival signal for the remaining cells after exposure to cytotoxic anticancer treatments. We highlight the need for a better understanding of the cellular markers and mechanisms involved in the involvement of HMGB1in cancer, and aim to provide a deeper understanding of its role in cancer progression.
... Meanwhile, CAF-derived HMGB1 was further confirmed to stimulate autophagy through MEK/ERK signaling in ERα-positive breast cancer cells, thus promoting tamoxifen resistance in cancer cells [117]. Similarly, an additional study revealed increased HMGB1 expression in breast cancer cells after coculture with CAFs, wherein the heightened HMGB1 levels increased resistance to doxorubicin in cancer cells through the potentiation of autophagy [118]. In addition, Liao et al. first reported that CAFs contribute to the development of cisplatin resistance in tongue cancer, which is also associated with the activation of autophagy mechanisms [119]. ...
Cancer-associated fibroblasts (CAFs), the main stromal component of the tumor microenvironment (TME), play multifaceted roles in cancer progression through paracrine signaling, exosome transfer, and cell interactions. Attractively, recent evidence indicates that CAFs can modulate various forms of regulated cell death (RCD) in adjacent tumor cells, thus involving cancer proliferation, therapy resistance, and immune exclusion. Here, we present a brief introduction to CAFs and basic knowledge of RCD, including apoptosis, autophagy, ferroptosis, and pyroptosis. In addition, we further summarize the different types of RCD in tumors that are mediated by CAFs, as well as the effects of these modes of RCD on CAFs. This review will deepen our understanding of the interactions between CAFs and RCD and might offer novel therapeutic avenues for future cancer treatments.
... The research indicates that CAFs and the collagen secreted by them are potential targets for the treatment of BC (127,128). Armornsupak et al. reported that CAFs can increase HMGB1 expression in breast cancer cells and promote doxorubicin resistance (129). It has been reported that MSC induces chemotherapy resistance (such as doxorubicin and 5-fluorouracil) via a CD9-dependent mechanism in BC and enhances the expression of drug-resistant proteins (BCRP and MDR1). ...
At present, the incidence rate of breast cancer ranks first among new-onset malignant tumors in women. The tumor microenvironment is a hot topic in tumor research. There are abundant cells in the tumor microenvironment that play a protumor or antitumor role in breast cancer. During the treatment of breast cancer, different cells have different influences on the therapeutic response. And after treatment, the cellular composition in the tumor microenvironment will change too. In this review, we summarize the interactions between different cell compositions (such as immune cells, fibroblasts, endothelial cells, and adipocytes) in the tumor microenvironment and the treatment mechanism of breast cancer. We believe that detecting the cellular composition of the tumor microenvironment is able to predict the therapeutic efficacy of treatments for breast cancer and benefit to combination administration of breast cancer.
... Following apoptosis, the release of high mobility group box-1 (HMGB1) into the TME is induced (155). HMGB1 activation of CAFs in breast cancer potentially mitigate the acquired chemotherapy resistance observed in patients with breast cancer (156). ...
Cancer-associated fibroblasts (CAFs) play a substantial role in the tumor microenvironment, exhibiting a strong association with the advancement of various types of cancer, including breast, pancreatic, and prostate cancer. CAFs represent the most abundant mesenchymal cell population in breast cancer. Through diverse mechanisms, including the release of cytokines and exosomes, CAFs contribute to the progression of breast cancer by influencing tumor energy metabolism, promoting angiogenesis, impairing immune cell function, and remodeling the extracellular matrix. Moreover, CAFs considerably impact the response to treatment in breast cancer. Consequently, the development of interventions targeting CAFs has emerged as a promising therapeutic approach in the management of breast cancer. This article provides an analysis of the role of CAFs in breast cancer, specifically in relation to diagnosis, treatment, drug resistance, and prognosis. The paper succinctly outlines the diverse mechanisms through which CAFs contribute to the malignant behavior of breast cancer cells, including proliferation, invasion, metastasis, and drug resistance. Furthermore, the article emphasizes the potential of CAFs as valuable tools for early diagnosis, targeted therapy, treatment resistance, and prognosis assessment in breast cancer, thereby offering novel approaches for targeted therapy and overcoming treatment resistance in this disease.
... As a key component of the TME, CAFs have been implicated in promoting and enabling chemoresistance in multiple cancer types, including breast cancer [8], squamous cell carcinoma [9], ovarian cancer, [10] colorectal cancer [11], and lung cancer [12]. The protumorigenic functions of CAFs are primarily driven by CAF-secreted growth factors and cytokines, such as insulin-like growth factor (IGF), hepatocyte growth factor (HGF), transforming growth factor-β (TGF-β), interleukin (IL)-6,-10, C-X-C motif chemokine ligand 12 (CXCL12) [13,14]. ...
Objectives:
A cure for cancer is out of reach for most patients due to chemoresistance. Cancer-associated fibroblasts (CAFs) play a vital role in cancer chemoresistance, but detailed understanding of the process particularly in chemoresistant lung cancer is lacking. In this study, we investigated programmed death-ligand 1 (PDL-1) as a potential biomarker for CAF-induced chemoresistance and evaluated its role and the underlying mechanisms of chemoresistance in non-small cell lung cancer (NSCLC).
Materials and methods:
A systemic search of gene expression profiles of multiple tissues in NSCLC was carried out to determine the expression intensities of traditional fibroblast biomarkers and CAF-secreted protumorigenic cytokines. PDL-1 expression in CAFs was analyzed by ELISA, Western blotting, and flow cytometry. Human cytokine array was used to identify specific cytokines secreted from CAFs. Role of PDL-1 in NSCLC chemoresistance was assessed using CRISPR/Cas9 knockdown and various functional assays including MTT, cell invasion, sphere formation, and cell apoptosis. In vivo experiments were conducted using a co-implantation xenograft mouse model with live cell imaging and immunohistochemistry.
Results:
We demonstrated that chemotherapy-stimulated CAFs promoted tumorigenic and stem cell-like properties of NSCLC cells, which contribute to their chemoresistance. Subsequently, we revealed that PDL-1 expression is upregulated in chemotherapy-treated CAFs and is associated with poor prognosis. Silencing PDL-1 expression suppressed CAFs' ability to promote stem cell-like properties and invasiveness of lung cancer cells, favoring chemoresistance. Mechanistically, an upregulation of PDL-1 in chemotherapy-treated CAFs led to an increase in hepatocyte growth factor (HGF) secretion, which stimulates cancer progression, cell invasion, and stemness of lung cancer cells, while inhibiting apoptosis.
Conclusion:
Our results show that PDL-1-positive CAFs modulate stem cell-like properties of NSCLC cells by secreting elevated HGF, thereby promoting chemoresistance. Our finding supports PDL-1 in CAFs as a chemotherapy response biomarker and as a drug delivery and therapeutic target for chemoresistant NSCLC.
... Human cancer-associated fibroblasts. CAFs and NFs were isolated from lung cancer tissues and benign tissues at least 5 cm from the tumor, respectively, using the outgrowth method described previously [27,28]. Briefly, sterile fresh surgical tissue was placed on ice in Dulbecco's modified Eagle medium (DMEM, Hyclone) supplemented with 10× penicillin-streptomycin (1000 U/ml penicillin and 1000 μg/ml streptomycin). ...
Cancer-associated fibroblasts (CAFs), the principal constituent of the heterogenous tumor microenvironment, have been shown to promote tumor progression; however, the underlying mechanism is still less clear. Here, we find that transgelin (TAGLN) protein levels increased in primary CAFs isolated from human lung cancer, compared with those in paired normal fibroblasts. Tumor microarrays (TMAs) revealed that increased stromal TAGLN levels correlates with more lymphatic metastasis of tumor cells. In a subcutaneous tumor transplantation model, overexpression of Tagln in fibroblasts also increased tumor cell spread in mice. Further experiments show that Tagln overexpression promoted fibroblast activation and mobility in vitro. And TAGLN facilitates p-p65 entry into the nucleus, thereby activating the NF-κB signaling pathway in fibroblasts. Activated fibroblasts promote lung cancer progression via enhancing the release of pro-inflammatory cytokines, especially interleukine-6 (IL-6). Our study revealed that the high levels of stromal TAGLN is a predictive risk factor for patients with lung cancer. Targeting stromal TAGLN may present an alternative therapeutic strategy against lung cancer progression.
... In addition, invasion from the spheroid observed in MDA-MB-213 P and BM sublines cultured in basal conditions could be explained by the possible presence of the autocrine function of the secreted HMGB1 from cancer cells inside the spheroid where hypoxia and glucose deprivation are presented (data not shown). These findings demonstrated that the extracellular role of HMGB1 on breast cancer progression is probably through promoting tumor cell migration and invasion as well as the acquired doxorubicin resistance via p-ERK mediated autophagy [23]. ...
Background
High-mobility group box 1 (HMGB1) is increased in breast cancer cells as the result of exposure to the secreted substances from cancer-associated fibroblasts and plays a crucial role in cancer progression and drug resistance. Its effect, however, on the expression of programmed death ligand 1 (PD-L1) in breast cancer cells has not been investigated. This study aimed to investigate the mechanism of HMGB1 through receptors for advanced glycation end products (RAGE) on cell migration/invasion and PD-L1 expression in breast cancer cells.
Methods
A 3-dimensional (3-D) migration and invasion assay and Western blotting analysis to evaluate the function and the mechanism under recombinant HMGB1 (rHMGB1) treatment with knockdown of RAGE using shRAGE and PI3K/AKT inhibitors was performed.
Results
The results revealed that rHMGB1 induced MDA-MB-231 cell migration and invasion. The knockdown of RAGE using shRAGE and PI3K/AKT inhibitors attenuated 3-D migration and invasion in response to rHMGB1 compared to mock cells. PD-L1 up-regulation was observed in both parental MDA-MB-231 (P) and MDA-MB-231 metastasis to bone marrow (BM) cells treated with rHMGB1, and these effects were alleviated in RAGE-knock down (KD) breast cancer cells as well as in PI3K/AKT inhibitor-treated cells.
Conclusions
Collectively, these findings indicate that HMGB1-RAGE through PI3K/AKT signaling promotes not only breast cancer cell invasion but also PD-L1 expression which leads to the destruction of the effector T cells. The attenuating HMGB1-RAGE-PI3K/AKT pathway may help to attenuate breast cancer cell aggressive phenotypes.
... Currently, a bidirectional interaction of HMGB1 between breast cancer cells and CAFs has been partially reported. Amornsupak et al. have found that CAFs can induce the production of HMGB1 in breast cancer cells and thus strengthen the chemoresistance to doxorubicin [106]. On the other hand, Chen et al. have reported that HMGB1 secreted by breast cancer cells can promote aerobic glycolysis and subsequently the activation of fibroblasts through the interaction with RAGE, and then the activated fibroblasts contribute to breast cancer cell metastasis by increasing lactate [53]. ...
HMGB1 is a member of highly conserved high mobility group protein superfamily with intracellular and extracellular distribution. Abnormal HMGB1 levels are frequently manifested in various malignant diseases, including breast cancer. Numerous studies have revealed the clinical value of HMGB1 in the diagnosis and therapy of breast cancer. However, the dual function of pro- and anti-tumor makes HMGB1 in cancer progression requires more profound understanding. This review summarizes the functions and mechanisms of HMGB1 on regulating breast cancer, including autophagy, immunogenic cell death, and interaction with the tumor microenvironment. These functions determine the strategies for the development of chemotherapy, radiotherapy, immunotherapy and combination therapies by targeting HMGB1 in breast cancer. Defining the mechanisms of HMGB1 on regulating breast cancer development and progression will facilitate the application of HMGB1 as a therapeutic target for breast cancer.
... Endo180 affects the contractility and viability of CAFs, but the mechanism by which it contributed to the metastasis of breast cancer remains unknown. According to Amornsupak et al. [313], CAFs increased the tolerance of breast cancer cells to adriamycin by upregulating HMGB1 in cancer cells, but the mechanism underlying the upregulation of this protein is unknown. Brechbuhl et al. [36] identified CD146-negative CAFs in ER-positive breast cancer and found that this subpopulation of CAFs downregulated the expression of ER in MCF-7 cells and confers tamoxifen resistance to cells. ...
The tumor microenvironment is proposed to contribute substantially to the progression of cancers, including breast cancer. Cancer‐associated fibroblasts (CAFs) are the most abundant components of the tumor microenvironment. Studies have revealed that CAFs in breast cancer originate from several types of cells and promote breast cancer malignancy by secreting factors, generating exosomes, releasing nutrients, reshaping the extracellular matrix, and suppressing the function of immune cells. CAFs are also becoming therapeutic targets for breast cancer due to their specific distribution in tumors and their unique biomarkers. Agents interrupting the effect of CAFs on surrounding cells have been developed and applied in clinical trials. Here, we reviewed studies examining the heterogeneity of CAFs in breast cancer and expression patterns of CAF markers in different subtypes of breast cancer. We hope that summarizing CAF‐related studies from a historical perspective will help to accelerate the development of CAF‐targeted therapeutic strategies for breast cancer.
... Several chemotherapeutic agents used in cancer treatment including DOX can induce the release of HMGB1 into the tumor environment after cell death and suggest that neutrophil cells and macrophages will be activated by cytokines as part of the innate immune response against cancer cells and will actively excrete HMGB1. Stromal fibroblast cells in breast cancer may also play a similar role in chemoresistance through upregulation of HMGB1 in cancer cells during chemotherapy-mediated cell death [56]. ...
... Due to damage, stress and inflammatory mediators that can be caused by toxic substances to cells, HMGB1 will be expressed both intracellularly and extracellularly with end results involved some cytokines in infection condition [57][58][59][60][61][62][63], metabolic disorder [64], allergy [65,66] and traumatic injury [67][68][69][70]. Expression of HMGB1 will cause an inflammatory process and affect the occurrence of ROS which will increase autophagy [56]. With the combination of the above processes, there is the release of extracellular vesicular (EV) calcifin and will unite with the extracellular matrix, which will eventually form calcium deposits in the cardiovascular system, including atherosclerotic calcification and calcification of aortic valve disease, ischemic heart. ...
Background
Doxorubicin (DOX) is a commonly used treatment for cancer and the mechanism of DOX-induced cardiomyocyte damage in cardiovascular disease is not fully understood. High-mobility group box 1 (HMGB1), strong induce proinflammatory cytokines via damage associated molecular pattern (DAMP) which its interaction with the receptor of advanced glycation end products (RAGE), that affect cytokine release, and angiogenesis via the role of HMBG1, HIF-1α and VEGF as an important regulator in these cardiac failure processes. Hypoxia-inducible factor-1α (HIF-1α) is plays an important role in the cellular response to systemic oxygen levels of cells and VEGF is an angiogenic factor and can stimulate cellular responses on the surface of endothelial cells will be described
Objective
The aim of this article is to comprehensively review the role of HMGB1, HIF-1α, and VEGF in DOX-induced Cardiovascular Disease and its molecular mechanisms.
Methods
The data in this study were collect by search the keyword combinations of medical subject headings (MeSH) of “HMGB1”, “HIF-1 α”, “VEGF”, “DOX” and “Cardiovascular disease” and relevant reference lists were manually searched in PubMed, EMBASE and Scopus database. All relevant articles in data base above were included and narratively discussed in this review article.
Results
Several articles were revealed that molecular mechanisms of the DOX in cardiomyocyte damage and related to HMGB1, HIF-1α and VEGF and may potential treatment and prevention to cardiovascular disease in DOX intervention.
Conclusion
HMGB1, HIF-1α and VEGF has a pivotal regulator in DOX-induce cardiomyocyte damage and predominantly acts through different pathways. The role of HMGB1 in DOX-induced myocardial damage suggests that HMGB1 is a mediator of DOX-induced damage. In addition, DOX can inhibit HIF-1α activity where DOX can decrease HIF-1α expression and HIF-1α is also responsible for upregulation of several angiogenic factors, including VEGF. VEGF plays an important role in angiogenesis and anti-angiogenesis both in vitro and in vivo and reduces the side effects of DOX markedly. In addition, the administration of anti-angiogenesis will show an inhibitory effect on angiogenesis mediated by the VEGF signaling pathway and triggered by DOX in cells.
