Mast cells in colorectal cancer tumour progression, angiogenesis, and lymphangiogenesis

The characteristics of the tumour cells, as well as how tumour cells interact with their surroundings, affect the prognosis of cancer patients. The resident cells in the tumour microenvironment are mast cells (MCs), which are known for their functions in allergic responses, but their functions in the cancer milieu have been hotly contested. Several studies have revealed a link between MCs and the development of tumours. Mast cell proliferation in colorectal cancer (CRC) is correlated with angiogenesis, the number of lymph nodes to which the malignancy has spread, and patient prognosis. By releasing angiogenic factors (VEGF-A, CXCL 8, MMP-9, etc.) and lymphangiogenic factors (VEGF-C, VEGF-D, etc.) stored in granules, mast cells play a significant role in the development of CRC. On the other hand, MCs can actively encourage tumour development via pathways including the c-kit/SCF-dependent signaling cascade and histamine production. The impact of MC-derived mediators on tumour growth, the prognostic importance of MCs in patients with various stages of colorectal cancer, and crosstalk between MCs and CRC cells in the tumour microenvironment are discussed in this article. We acknowledge the need for a deeper comprehension of the function of MCs in CRC and the possibility that targeting MCs might be a useful therapeutic approach in the future.

dysregulated gene expression, and anomalies in the epigenome, requires the coordinated action of several processes (3). However, altered cells are regularly removed through immune surveillance, which stops tumour development (4). Through intricate methods, many immunosuppressive cells can evade immune system detection, allowing for ongoing tumour growth. Tumour development requires angiogenesis, and lymphangiogenesis is crucial to lymph node metastasis (5,6). Mast cells are found in all vertebrates (7) and were described and originally named by Paul Ehrlich in 1878 (8). Westphal first postulated that MCs played a protumourigenic role in 1891 (9). MCs are derived from hematopoietic stem cells that are CD34+ (10) and CD117+ (KIT) and can be separated into two groups based on their composition: M(T) and M (Tc). Mc(T) granules are rich in trypsin and are mainly located in the mucosa of the gastrointestinal and respiratory tracts (11,12). On the other hand, Mc(TC) particles contain trypsin, chymotrypsin, and carboxypeptidase and are mainly located in the submucosa, connective tissue, near blood vessels, and lymphatic vessels (12). Mast cells, which act as the barrier between the host and the outside environment, can enhance host defense against infections by controlling the immune response (13). Mast cells are also critical immune cells that can secrete cytokines that alter tumour growth in the inflammatory milieu, and they play a significant role in hypersensitivity, particularly type I hypersensitivity. Proteases (including trypsin and chymase), histamine, cytokines, chemokines, and angiogenic factors are among the bioactive mediators found in the cytoplasm of mast cells (11,14). The conventional pathway, which is mediated by IgE binding to the FcRI receptor on the surface of mast cells, is the most well-known method of initiating MC degranulation; however, the activation of C3a and C5a in the inflammatory milieu can directly induce MC degranulation (15). Mast cells secrete a variety of bioactive mediators that can inhibit and promote tumours (16). The heterogeneity of mediators released by MCs depends on the tissue, environment, and different pathways that activate MCs, such as IgE-dependent activation, IgG immune complex crosslinking with FcgRIII, C3a and C5a complement receptor activation, stem cell factor (SCF)-bound c-kit receptor, and TLR 2 (toll-like receptor 2) activation (17). It is interesting to note that mast cells produce naturally occurring and immunemediated proangiogenic factors that help blood vessels form (e.g., VEGF-A, endothelin-1, GM-CSF, and CXCL 8) (18,19). In the tumour microenvironment, these cells can also release compounds that promote lymphangiogenesis, such as VEGF-C and VEGF-D (9). The role of MCs in CRC is still controversial and uncertain. However, understanding the molecular mechanisms underlying the interaction between MCs, cancer cells, and other elements of the tumour microenvironment may help in the search for a way to interfere with the interaction between cancer cells and other cells to stop the growth and reproduction of cancer cells.

MC growth and biological function
Half a billion years ago, the innate immune system included MCs, which exerted antiparasitic and antibacterial effects in the host, and they can be found in the hemolymph of the ascidian (sea squirts) (20, 21). MCs are mainly derived from the myeloid lineage of bone marrow hematopoietic stem cells (22). CD34 + /CD117 + pluripotent MC progenitors (MCps) leave the bone marrow, migrate and colonize target tissues (e.g., gastrointestinal tract, skin, perivascular space, perineural connective tissue and respiratory tract) via specific integrin and chemokine receptors (23-26). Subsequently, in response to stem cell factor (SCF), IL-3, IL-4, IL-9, IL-10, TGF-b, and IL-33, MCps develop into MCs with dense granules (27-32). A recent study showed that MCps and mature MCs express some of the same chemokine receptors, such as CXCR4 and CCR1, suggesting that mature mast cells can still migrate to other tissues after maturation (33). MC surface receptors bind to tumour-derived cytokines and growth factors, which recruits these cells into the tumour microenvironment. For example, SCF produced by tumour cells bind to the c-Kit receptor on mast cells (34-36). Several chemokines derived from tumours (CCL2, CCL5, CCL11, CCL15, CXCL1, CXCL2, CXCL10 and CXCL12) can activate mast cell receptors (CCR2, CCR3, CXCR2, CXCR3 and CXCR4) to induce MC migration (34, 37-43). On the other hand, VEGF, platelet-derived growth factor AB (PDGF-AB), basic fibroblast growth factor (bFGF), and adrenomedullin (AM) produced by tumour cells can induce mast cell chemotaxis (44). Mast cells play an important role in innate and adaptive immunity (45). Mast cells are among the first cells to come into contact with pathogens, and so they are reliable prerequisite cells for preventing infection in humans (46). Mast cells can fight pathogens through direct antibacterial, antiviral and antiparasitic effects (e.g., the release of multiple antimicrobial peptides, killing bacteria after binding to complement or IgG Fc receptors, and endocytosis) (47-50). The more important role of mast cells in innate immunity is to recruit other innate immune cells, such as neutrophils, eosinophils and macrophages, to the site of infection (51-53); thus, multiple immune cells come together to better clear pathogens. On the other hand, several costimulatory molecules (CD40L, OX40L, CD80, and CD86) on mast cells and the various cytokines (IL-4, IL-5, IL-6, IL-13 and IL-33) they produce can influence the biological behavior of TH2 cells and B cells and modulate regulatory T cells (Tregs), thus regulating adaptive immunity (46). For example, MC-derived IL-25, IL-33, and TSLP can activate antigen-presenting cells (e.g., DCs) to eventually regulate the functional status of TH2 cells (54). In conclusion, mast cells play an important role in the protection of human health and in the pathophysiology of various diseases (e.g., cancer), IgEdriven allergic diseases, cardiovascular diseases, autoimmune diseases and cancer) (55).

The controversial role of MCs in cancer
Depending on the kind, stage, grade, and size of the tumour, as well as their microanatomical placement inside the tumour, tumour-associated mast cells (TAMCs) can have pro-or antitumourigenic effects on the host (56). However, in a some circumstances, these cells do not seem to have any impact on the development or progression of tumours (57-59). The protumour activity of MCs and the link between TAMCs and poor clinical outcomes in a variety of cancers, including Hodgkin lymphoma, gastric cancer (GC), pancreatic cancer, cholangiocarcinoma, and bladder cancer, are supported by a number of research investigations. MC infiltration is associated with a worse prognosis and lower relapse-free survival rates in Hodgkin's lymphoma (60-62). In vitro experiments showed that Hodgkin's lymphoma could promote tumour cell proliferation through CD30L-CD30 interactions between mast cells and cancer cells (60, 63). Similar results have been observed in gastric cancer, in which the presence of tumour-infiltrating MCs is related to tumour progression and independently predicts a lower overall survival rate (64-66). Tumour-derived adrenomedullin (ADM) stimulated mast cell production of IL-17A, which can boost GC cell proliferation and block GC cell death in vitro (66). Intriguingly, pancreatic cancer cells have been shown to attract MCs to the tumour microenvironment. MCs then aid in tumour cell proliferation and invasion, hastening disease development (67). MC infiltration is enhanced along with carcinogenesis in cholangiocarcinoma (68) and bladder cancer (69). Mast cells in these tumours have protumourigenic effects by influencing tumour biology, including angiogenesis, lymphangiogenesis, invasiveness, and tumour cell proliferation, which ultimately results in a poor prognosis for patients.
Research linking the presence of mast cells to various tumour types seem to be contradictory. High concentrations of peritumoural mast cells were linked to a poor prognosis in prostate cancer, although mast cell densities inside tumours were an independent favorable prognostic predictor (70-72). The different anatomical placements of the mast cells might be the cause of these opposing effects (peritumoural vs. intratumoural). The accumulation of mast cells in the peritumoural compartment during the development of a castration-resistant prostate tumour ultimately resulted in tumour palindromia (70). Mast cells have been linked with a favorable prognosis in breast carcinomas in some studies (73-77) but not all of them (78)(79)(80). There is also a high degree of intertumour and intratumour heterogeneity among patients (81). In lung adenocarcinoma, a higher MC count was associated with poor prognosis in stage I NSCLC (82). In contrast to another study, a low density of peritumoural mast cells was associated with a worse prognosis in stage I lung adenocarcinoma (83). In skin cancers, human and animal studies targeting the function of mast cells and their mediators have obtained controversial outcomes (84). Mast cell-derived serine proteases inhibit the growth of melanoma (85); however, data have also reported that MCs are associated with poor prognosis (86) and resistance to immune therapy (87).

TAMCs in tumour angiogenesis and lymphangiogenesis
Angiogenesis, which is the growth of new blood vessels, is essential to many physiological processes that take place as the human body develops (5). Lymphangiogenesis, which is the development of new lymphatic vessels, is a process that is active in some diseases (wound healing, chronic inflammation, tumour metastasis, etc.) (88). The ratio of substances that stimulate angiogenesis and lymphangiogenesis to those that prevent it determines the rate (89). It is interesting to note that the regulation of lymphangiogenesis and angiogenesis is mediated by innate and adaptive immune cells, including mast cells (90). In 1971, Judah Folkman proposed that angiogenesis was necessary for the growth of tumours (91), and he later proposed that mast cells may be a major source of substances that promote angiogenesis (92). Similarly, tumour-associated lymphangiogenesis plays an integral role in lymph node metastasis and tumour progression (93). Many experiments have demonstrated that pro-angiogenic factors (VEGF-A, VEGF-B) (94)(95)(96)(97), and pro-lymphangiogenic factors (VEGF-C and -D) (43, 94) are synthesized by mast cells. VEGF receptor 2 (VEGFR-2) is expressed by blood endothelial cells (BECs), and VEGF-A activates it to carry out its intended tasks (98). Since VEGFs induces mast cell chemotaxis by binding to the VEGFR-1 and VEGFR-2 receptors on their surface, mast cells serve as both the source and the target (89,99). Lymphangiogenesis depends on VEGF-C and VEGF-D binding to their receptor VEGFR-3 (100, 101). In addition to playing a crucial switching role in tumourassociated angiogenesis (102), angiopoietins (Angs) and their endothelial cell receptor Tie2 can encourage the growth of lymphatic vessels (103). Ang1 expression by pericytes is essential for vascular maturation, Ang2 is produced by ECs, and both of these factors agonize Tie2 under certain conditions (104, 105). Mast cellderived chymotrypsin converts Ang1 to Ang2 and accelerates angiogenesis (106). Tie1 and Tie2 are expressed on the surface of human lung mast cells (HLMCs), and the binding of Ang1 to Tie2 can cause mast cell migration (107). When stem cell factor (SCF) binds to c-KitR on the MC surface, the c-KitR pathway is activated, inducing MC degranulation and the release of trypsin and proangiogenic cytokines (such as VEGF, PDGF, and FGF-2) (108, 109). Trypsin produced by mast cells can directly stimulate endothelial cell growth (110) or indirectly activate matrix-metalloproteases (MMPs) and plasminogen activator (PA) to degrade the extracellular matrix, providing space for neovascularization and facilitating the invasion and metastasis of cancer cells (36, 111). Moreover, trypsin can activate protease-activated receptor 2 (PAR-2) (112), which is expressed on endothelial cells in the blood vessel wall (113). When PAR-2 is activated, endothelial cells multiply, and proangiogenic chemicals, including IL-6 and granulocyte macrophage colonystimulating factor, are released (114). Notably, IL-1 can trigger human mast cells to produce CXCL8/IL-8, effectively increasing angiogenesis (115). Extracellular adenosine is elevated in the tumour microenvironment because of hypoxia, and this factor can activate adenosine receptors on the surface of mast cells, which increases the production of VEGF and CXCL8/IL-8 (116), ultimately promoting angiogenesis and lymphangiogenesis.

Mast cells and prognosis in CRC
The role of mast cells in colorectal cancer progression is controversial. Many researchers have investigated the correlation between MCs and CRC patient prognosis (Table 1). Some authors believe that MCs are correlated with a good prognosis (22, 117, 118), while others believe that mast cells are not associated with prognosis (59, 119, 120), but most studies suggest that mast cells are associated with reduced survival rates (2,(121)(122)(123).
Song et al. analyzed pathological tissues from 164 CRC patients and found that high mast cell density (MCD) levels were significantly associated with longer overall survival of patients (22). Mehdawi et al. (117) observed that fewer MCs were found in cancer tissue from 72 CRC patients than in normal colon tissue and that patients with relatively higher MCD in cancer tissue had a significantly longer overall survival.
However, Mao et al. (123) confirmed that MCD was an independent prognostic factor, and low tumour infiltration MCD was associated with increased overall survival, which may be due to the association of low MCD with a stronger immune response to aid prolonged survival in patients with a low MCD, MCD has also been shown to predict survival in stage II and III CRC patients treated with adjuvant chemotherapy. Suzuki et al. (121) reported that high peritumoural MC infiltration was a significantly unfavorable prognostic factor in 135 patients with colorectal liver metastasis (CRLM) who underwent liver resection, and the number of MCs in liver metastatic lesions could significantly predict the prognosis of CRLM patients and was an indication for treatment. Wu et al. (2) showed that MC infiltration was significantly associated with sex, lymph node status, and American Joint Committee on Cancer stage, and high MC infiltration can serve as an independent biological marker to predict poor survival in colorectal cancer patients. Thus, the identification of patients with high risk of tumour progression can be achieved by immunohistochemical analysis of tumourinfiltrating mast cells, thus optimizing personalized treatment for CRC patients.
In contrast, Xia et al. (119) observed that mast cell counts in adjacent normal colon mucosa were associated with pathological classification, distant metastasis, and liver metastasis but were not a prognostic factor. Instead, mast cell counts in the invasive margin showed no correlation with clinicopathological parameters or overall survival. Zhao et al. (120) reported that circulating mast progenitor cell (MCp) levels are low in CRC patients and are significantly associated with CRC progression, and the frequency of MCps may be an independent indicator of the aggressiveness of CRC in patients and may be used to distinguish between patients with early and advanced CRC. However, mast cells in tumour tissue are not associated with CRC progression.
These conflicting results stem in part from the high heterogeneity of studies on MCs and CRC. For example, different tumour regions have been examined in many studies on MCs and CRC, and some studies examined the surrounding tumour regions, while others examined the central tumour areas, and many studies did not report the tumour regions examined, making it difficult to compare. However, there is a link between the distribution of MCs and the prognosis of CRC patients. MC infiltration was defined as a favorable independent prognostic factor in CRC patients (124); however, a large number of MCs confined to the tumour periphery is associated with tumour progression (121,125,126). On the other hand, stage IIIB colon cancer was shown by Xia et al. (59) to have mast cell numbers that varied depending on where in the tumour they were located, and the interstitium of primary colon cancer had fewer mast cells than the neighboring mucosa.
In addition to the localization of mast cells, MCs from different tissues were analyzed by transcriptional profiling, and MCs showed large transcriptional heterogeneity between different tissues (127). MC degranulation status also plays an important role in the prognosis of CRC patients. A recent study showed that the proportion of degranulated mast cells (observed by morphology) was increased in patients with metastatic colorectal cancer, while the proportion of intact mast cells was increased in the nonmetastatic group (128). This may be related to the tumourigenic activity of some products released during MC degranulation. Recently, it was found that in NSCLC, TAMCs were divided into 2 subgroups based on alphaE integrin (CD103) expression, and CD103+ cells were more likely to interact with T cells and were closer to cancer cells, thus emphasizing the nonnegligible heterogeneity of MCs in cancer (129). In most studies, however, characterization of the MC phenotype was not described in detail.
Therefore, to better understand how MCs affect the prognosis of CRC patients, it is important to focus not only on MC counts but also on understanding their localization, detection methods, degranulation status, degranulation products, and phenotype. For example, we could apply new multiomics, single-cell sequencing and imaging mass cytometry technologies to examine colon cancerassociated MCs and provide a better understanding of the various biological behaviors of mast cells in the tumour microenvironment. Ducroc et al. (113) demonstrated that PAR-2 was expressed in several colon cancer cell lines, and MC-derived trypsin activation of PAR-2 was significantly associated with cell proliferation. The mitogen-activated protein kinase/extracellular signal-associated kinase (MEKK) and mitogen-activated protein kinase (MAPK) pathways are briefly phosphorylated as a result of PAR-2 activation, which promotes the growth of colon cancer cells by increasing the production of cyclooxygenase-2 (COX-2) and prostaglandin E2 (PGE2) (138). Therefore, the proliferation of CRC cells and the growth of associated blood vessels can be inhibited by trypsin inhibitors (gabexate) and c-KitR inhibitors Multiple roles of MCs in colorectal tumours. The release of multiple factors, such as vascular endothelial growth factor, IFN, CXCL8, histamine, nitric oxide, and PGD2, as well as interactions with various populations of the immune system, including CD8+ T cells (130) and MDSCs (131), result in MCs shaping the tumour microenvironment (TME) in different ways and exerting antitumour and protumour effects depending on the context. MCs influence tumour aggressiveness through the release of trypsin and MMPs (111), among other substances. On the other hand, colon tumour cells influence the biological behavior of MCs by various means, such as the release of IL-33 (132) and the activation of Sigle (133), which is surface receptor of MCs.
(imatinib, macitinib) (139, 140). On the other hand, activated c-Kit activates the downstream Wnt/b-catenin signaling pathway (141), and Wnt is abundantly expressed in colorectal tumour cells (142), ultimately activating the b-catenin signaling pathway in mast cells in colorectal tumours, while b-catenin stimulates protease maturation and expression in mast cells, and activated b-catenin mediates bone marrow-derived mast cell support of colon cancer (143). Therefore, by blocking the c-Kit receptor with drugs, the bcatenin signaling pathway in MCs will also be inhibited (144), thus inhibiting tumour growth.
In addition, mast cells promote the development of colorectal cancer through several mechanisms. Activation of mucosal mast cells (MMCs) leads to the recruitment of large numbers of CD11b +Gr1+ inflammatory cells into colonic tissue, and MMCs can regulate the activity of CD11b+Gr1+ cells to promote the development of CRC (145). Mast cells can increase the suppressive properties of splenic-derived monocyte MDSCs through IFNg and nitric oxide production, and the two cell populations interact with each other through CD40:CD40L crosssignaling, which is an axis that is tasked with forming a proinflammatory microenvironment that leads to the production of mediators (TNFa, IL6, CCL-2) (131). Notably, CCL-2 can mediate the migration and activation of MDSCs in tumours (146). Furthermore, mast cells can induce the migration of MDSCs, which can cause immune escape in tumour cells and further cause tumour development (131). On the other hand, mast cells can upregulate RhoA expression in colon cancer cells to activate the Rho/ROCK signaling pathway in tumour cells (147), leading to increased cell mobility (148) and ultimately promoting CRC invasion. The MAPK pathway mediates cell proliferation and differentiation, and many inflammatory factors can activate protein kinases in the MAPK signaling pathway, such as ERK and JNK, which promote tumour progression (149,150). Mast cells promote tumour-associated angiogenesis through the MAPK/Rho-GTPase/ STAT pathway, leading to the development of colon cancer (147). In the hypoxic microenvironment of colorectal cancer, mast cells synthesize hypoxia-inducible factor-1a (HIF-1a) to ensure their own degranulation potential; thus, MC-derived HIF-1a is associated with the release of inflammatory factors (VEGF, IL-6, TGF-b, etc.), and MCs can promote angiogenesis and tumour metastasis by synthesizing HIF-1a (151).
Mast cells affect the development of colon cancer cells, and tumour cells affect the biological behavior of mast cells. YU et al. (152) showed that transcriptome profiling of combined cultures of HT 29 colon cancer cells and MCs showed active expression of MMP-2, VEGF-A, PDGF-A, COX 2, NOTCH1, and ISG 15 by comparing MCs with controls, which revealed how HT 29 makes MCs tumourigenic in the initial stage. These findings provide a new method to study the difference between MCs associated with colon cancer and MCs in normal tissue with a 3D coculture model (152). Many organs express IL-33, which is a cytokine belonging to the IL-1 family (153). The main producers of IL-33 are nonhematopoietic cells such as endothelial cells, smooth muscle cells, adipocytes, myofibroblasts, and epithelial cells (154,155). Of note, IL-33 is expressed in the tumour epithelium of human colorectal cancer adenomas and carcinomas, and IL-33 activates mast cells and subepithelial myofibroblasts (SEMFs) to express and release ECM components and remodeling proteins, growth factors and angiogenesis modulators, and cytokines to develop a tissue microenvironment that is conducive to polyposis (132). Siglecs are a class of receptors that resemble immunoglobulins and bind sialic acid, and they come in many isoforms and are mostly expressed on immune cells (156). Siglec-6 is the isoform that is the most highly expressed in human MCs, which also express Siglec-3, Siglec-5, Siglec-6, Siglec-7, and Siglec-8 (157, 158). Yu et al. (133) discovered that Siglec-6 was a functional inhibitory receptor for MCs, and Siglec-6 was upregulated on MCs when colon cancer cells (HT29 and co2) were cocultured with MCs, suggesting that MC activity may be regulated through Siglec-6 in the tumour microenvironment of colorectal cancer and demonstrated Siglec-6 expression on human CRC tissue for the first time.
IL-17 is an inflammatory cytokine that is notably increased in gastrointestinal inflammation and cancer (159). The intestine contains many cells that express IL-17, such as innate-like T cells, ab and gd T cells, NKT and NK cells, macrophages, granulocytes and mast cells (160-162). Chen et al. (163) found that in histaminedeficient intestinal immunity, intestinal MCs expressing IL-17 were expanded in response to food allergy, while MCs expressing IL-17 were actively mobilized, recruited MDSCs to the intestinal mucosa and suppressed CD8 T-cell activity. Notably, these susceptibility factors that increase tumourigenesis can be reversed by histamine therapy, and histamine appears to prevent MC polarization into IL-17-secreting cells (163). Food allergy can affect colorectal carcinogenesis through mast cells and needs further study.
Interestingly, there have recently been experiments (130) demonstrating that MCs can promote or hinder CRC development, and this difference may vary depending on the type of stimulus that promotes CRC. Activated MCs reduce the number of CD8 + T cells in tumours and promote the progression of colitisdependent (colitis-associated (CA)-CRC), but they inhibit colitisindependent (sporadic (s)CRC) development (130). On the other hand, Iwanaga et al. (164) demonstrated that mast cells strongly expressed H-PGDS in the inflamed colon, and the release of PGD2 inhibits colitis and CRC generation by attenuating TNF a signaling. Cystatin C is an endogenous lysosomal cysteine protease inhibitor, and serum cystatin C can be used as a marker for the diagnosis of renal dysfunction (165). Serum cystatin C levels are associated with a variety of diseases, including tumours (166). Recently, it was shown that mast cell-derived cystatin C can specifically induce endoplasmic reticulum stress (ERS) in CRC cells, thereby inhibiting CRC development (22).

Conclusions
Previously neglected MCs are gradually becoming protagonists in tumourigenesis, and increasing evidence demonstrates their importance in tumour prognosis and therapeutic efficacy. Despite this awareness, the role and pathogenic mechanisms of MCs in tumours are still far from understood. This is mainly reflected in the contradictory results of many studies. This is a result of mast cells having context-dependent phenotypes and plasticity, which are sensitive to the suddenly changing microenvironment. In addition, many studies on the association between MCs and CRC merely showed the number or density of mast cells without addressing other important features, such as the degranulation status of MCs, tumour localization, the characteristics of secreted cytokines and proteases, and crosstalk between associated immune cells and colon cancer cells. MC is closely linked to angiogenesis, lymphangiogenesis, and the progression of CRC, and it is likely to provide targets for new therapies in the future. Therefore, we urgently need higher quality studies to fully understand the biological behavior of MCs in CRC patient tumours.

Author contributions
YL and NL designed the study. XXL wrote the manuscript. HW and XYL consulted relevant materials and drew pictures. All authors contributed to manuscript revision, read, and approved the submitted version.

Funding
This work was partly supported by the National Natural Science Foundation of China (No. 81974088)and the Key Program of the National Natural Science Foundation of China (grant no. 82230021).

Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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