Calculus bovis inhibits M2 tumor-associated macrophage polarization via Wnt/β-catenin pathway modulation to suppress liver cancer

BACKGROUND Calculus bovis(CB),used in traditional Chinese medicine,exhibits anti-tumor effects in various cancer models.It also constitutes an integral component of a compound formulation known as Pien Tze Huang,which is indicated for the treatment of liver cancer.However,its impact on the liver cancer tumor microenvironment,particularly on tumor-associated macrophages(TAMs),is not well understood.AIM To elucidate the anti-liver cancer effect of CB by inhibiting M2-TAM polarization via Wnt/β-catenin pathway modulation.METHODS This study identified the active components of CB using UPLC-Q-TOF-MS,evaluated its anti-neoplastic effects in a nude mouse model,and elucidated the underlying mechanisms via network pharmacology,transcriptomics,and molecular docking.In vitro assays were used to investigate the effects of CB-containing serum on HepG2 cells and M2-TAMs,and Wnt pathway modulation was validated by real-time reverse transcriptase-polymerase chain reaction and Western blot analysis.RESULTS This study identified 22 active components in CB,11 of which were detected in the bloodstream.Preclinical investigations have demonstrated the ability of CB to effectively inhibit liver tumor growth.An integrated approach employing network pharmacology,transcriptomics,and molecular docking implicated the Wnt signaling pathway as a target of the antineoplastic activity of CB by suppressing M2-TAM polarization.In vitro and in vivo experiments further confirmed that CB significantly hinders M2-TAM polarization and suppresses Wnt/β-catenin pathway activation.The inhibitory effect of CB on M2-TAMs was reversed when treated with the Wnt agonist SKL2001,confirming its pathway specificity.CONCLUSION This study demonstrated that CB mediates inhibition of M2-TAM polarization through the Wnt/β-catenin pathway,contributing to the suppression of liver cancer growth.

The heterogeneity of tumor-associated macrophages and strategies to target it

Tumor-associated macrophages(TAMs)are emerging as targets for tumor therapy because of their primary role in promoting tumor progression.Several studies have been conducted to target TAMs by reducing their infiltration,depleting their numbers,and reversing their phenotypes to suppress tumor progression,leading to the development of drugs in preclinical and clinical trials.However,the heterogeneous characteristics of TAMs,including their ontogenetic and functional heterogeneity,limit their targeting.Therefore,in-depth exploration of the heterogeneity of TAMs,combined with immune checkpoint therapy or other therapeutic modalities could improve the efficiency of tumor treatment.This review focuses on the heterogeneous ontogeny and function of TAMs,as well as the current development of tumor therapies targeting TAMs and combination strategies.

Research progress of tumor-associated macrophages in immune checkpoint inhibitor tolerance in colorectal cancer

The relevant mechanism of tumor-associated macrophages(TAMs)in the treatment of colorectal cancer patients with immune checkpoint inhibitors(ICIs)is discussed,and the application prospects of TAMs in reversing the treatment tolerance of ICIs are discussed to provide a reference for related studies.As a class of drugs widely used in clinical tumor immunotherapy,ICIs can act on regulatory molecules on cells that play an inhibitory role-immune checkpoints-and kill tumors in the form of an immune response by activating a variety of immune cells in the immune system.The sensitivity of patients with different types of colorectal cancer to ICI treatment varies greatly.The phenotype and function of TAMs in the colorectal cancer microenvironment are closely related to the efficacy of ICIs.ICIs can regulate the phenotypic function of TAMs,and TAMs can also affect the tolerance of colorectal cancer to ICI therapy.TAMs play an important role in ICI resistance,and making full use of this target as a therapeutic strategy is expected to improve the immunotherapy efficacy and prognosis of patients with colorectal cancer.

MicroRNA-206 as a promising epigenetic approach to modulate tumor-associated macrophages in hepatocellular carcinoma

This letter comments on the recently published manuscript by Huang et al in the World Journal of Gastroenterology,which focused on the immunomodulatory effect of Calculus bovis on hepatocellular carcinoma(HCC)tumor microenvironments(TME)by inhibiting M2-tumor-associated macrophage(M2-TAM)polarization via Wnt/β-catenin pathway modulation.Recent research highlights the crucial role of TAMs and their polarization towards the M2 phenotype in promoting HCC progression.Epigenetic regulation,particularly through microRNAs(miR),has emerged as a key factor in modulating immune responses and TAM polarization in the TME,influencing treatment responses and tumor progression.This editorial focuses on miR-206,which has been found to inhibit HCC cell proliferation and migration and promote apoptosis.Moreover,miR-206 enhances anti-tumor immune responses by promoting M1-polarization of Kupffer cells,facilitating CD8+T cell recruitment and suppressing liver cancer stem cell expansion.However,challenges remain in understanding the precise mechanisms regulating miR-206 and its potential as a therapeutic agent.Targeting epigenetic mechanisms and improving strategies,whether through pharmacological or genetic approaches,offer promising avenues to sensitize tumor cells to chemotherapy.Understanding the intricate interactions between cancer and non-coding RNA regulation opens new avenues for developing targeted therapies,potentially improving HCC prognosis.

Abnormally activated wingless/integrated signaling modulates tumor-associated macrophage polarization and potentially promotes hepatocarcinoma cell growth

In this article,we comment on the article by Huang et al.The urgent development of new therapeutic strategies targeting macrophage polarization is critical in the fight against liver cancer.Tumor-associated macrophages(TAMs),primarily of the M2 subtype,are instrumental in cellular communication within the tumor microenvironment and are influenced by various signaling pathways,including the wingless/integrated(Wnt)pathway.Activation of the Wnt signaling pathway is pivotal in promoting M2 TAMs polarization,which in turn can exacerbate hepatocarcinoma cell proliferation and migration.This manuscript emphasizes the burgeoning significance of the Wnt signaling pathway and M2 TAMs polarization in the pathogenesis and progression of liver cancer,highlighting the potential therapeutic benefits of inhibiting the Wnt pathway.Lastly,we point out areas in Huang et al’s study that require further research,providing guidance and new directions for similar studies.

Correlation of tumor-associated macrophage density and proportion of M2 subtypes with the pathological stage of colorectal cancer

BACKGROUND Colorectal cancer(CRC)is a prevalent global malignancy with complex prognostic factors.Tumor-associated macrophages(TAMs)have shown paradoxical associations with CRC survival,particularly concerning the M2 subset.AIM We aimed to establish a simplified protocol for quantifying M2-like TAMs and explore their correlation with clinicopathological factors.METHODS A cross-sectional study included histopathological assessment of paraffinembedded tissue blocks obtained from 43 CRC patients.Using CD68 and CD163 immunohistochemistry,we quantified TAMs in tumor stroma and front,focusing on M2 proportion.Demographic,histopathological,and clinical parameters were collected.RESULTS TAM density was significantly higher at the tumor front,with the M2 proportion three times greater in both zones.The tumor front had a higher M2 proportion,which correlated significantly with advanced tumor stage(P=0.04),pathological nodal involvement(P=0.04),and lymphovascular invasion(LVI,P=0.01).However,no significant association was found between the M2 proportion in the tumor stroma and clinicopathological factors.CONCLUSION Our study introduces a simplified protocol for quantifying M2-like TAMs in CRC tissue samples.We demonstrated a significant correlation between an increased M2 proportion at the tumor front and advanced tumor stage,nodal involvement,and LVI.This suggests that M2-like TAMs might serve as potential indicators of disease progression in CRC,warranting further investigation and potential clinical application.

Inhibition of M2 tumor-associated macrophages polarization by modulating the Wnt/β-catenin pathway as a possible liver cancer therapy method

The problem of liver cancer is becoming increasingly important due to the epi-demic of metabolic diseases and persistent high alcohol consumption.This deter-mines great attention to the development and improvement of methods for early diagnosis and treatment of liver cancer.Huang et al presented a study in the World Journal of Gastroenterology,in which they showed that the use of the traditional Chinese medicine Calculus bovis(CB)can suppress tumor growth in mice by inhibiting M2 tumor-associated macrophages(TAM)through modulating the activity of the Wnt/β-catenin pathway.The interaction of CB components with the Wnt/β-catenin pathway,M2 TAM polarization,and tumor dynamics were studied using network pharmacology,transcriptomics,and molecular docking.It is now generally accepted that the polarization of TAM and the differentiation of the functions of M1 and M2 phagocytes are of great importance for the progression of neoplasms.It is assumed that M2 TAM promote proliferation and migration of tumor cells.Attempts to medicinally influence the Wnt/β-catenin pathway in order to modulate phagocyte polarization now belong to one of the most promising areas of immunotherapy of oncological diseases.Undoubtedly,the work of the Chinese authors deserves attention and further development.

Role of tumor-associated macrophages in common digestive system malignant tumors

Many digestive system malignant tumors are characterized by high incidence and mortality rate.Increasing evidence has revealed that the tumor microenvironment(TME)is involved in cancer initiation and tumor progression.Tumor-associated macrophages(TAMs)are a predominant constituent of the TME,and participate in the regulation of various biological behaviors and influence the prognosis of digestive system cancer.TAMs can be mainly classified into the antitumor M1 phenotype and protumor M2 phenotype.The latter especially are crucial drivers of tumor invasion,growth,angiogenesis,metastasis,immunosuppression,and resistance to therapy.TAMs are of importance in the occurrence,development,diagnosis,prognosis,and treatment of common digestive system malignant tumors.In this review,we summarize the role of TAMs in common digestive system malignant tumors,including esophageal,gastric,colorectal,pancreatic and liver cancers.How TAMs promote the development of tumors,and how they act as potential therapeutic targets and their clinical applications are also described.

Role of Cyclin D1b in Inducing Macrophages Toward a Tumor-associated Macrophage-like Phenotype in Murine Breast Cancer

Objective:Tumor-associated macrophages(TAMs)of the M2 phenotype are frequently associated with cancer progression.Invasive cancer cells undergoing epithelial-mesenchymal transition(EMT)have a selective advantage as TAM activators.Cyclin D1b is a highly oncogenic splice variant of cyclin D1.We previously reported that cyclin D1b enhances the invasiveness of breast cancer cells by inducing EMT.However,the role of cyclin D1b in inducing macrophage differentiation toward tumor-associated macrophage-like cells remains unknown.This study aimed to explore the relationship between breast cancer cells overexpressing cyclin Dlb and TAMs.Methods:Mouse breast cancer 4T1 cells were transfected with cyclin D1b variant and co-cultured with macrophage cells in a Transwell coculture system.The expression of characteristic cytokines in differentiated macrophages was detected using qRT-PCR,ELISA and zymography assay.Tumor-associated macrophage distribution in a transplanted tumor was detected by immunofluorescence staining.The proliferation and migration ability of breast cancer cells was detected using the cell counting kit-8(CCK-8)assay,wound healing assay,Transwell invasion assay,and lung metastasis assay.Expression levels of mRNAs were detected by qRT-PCR.Protein expression levels were detected by Western blotting.The integrated analyses of The Cancer Genome Atlas(TCGA)datasets and bioinformatics methods were adopted to discover gene expression,gene coexpression,and overall survival in patients with breast cancer.Results:After co-culture with breast cancer cells overexpressing cyclin D1b,RAW264.7 macrophages were differentiated into an M2 phenotype.Moreover,differentiated M2-like macrophages promoted the proliferation and migration of breast cancer cells in turn.Notably,these macrophages facilitated the migration of breast cancer cells in vivo.Further investigations indicated that differentiated M2-like macrophages induced EMT of breast cancer cells accompanied with upregulation of TGF-β1 and integrinβ3 expression.Conclusion:Breast cancer cells transfected with cyclin D1b can induce the differentiation of macrophages into a tumor-associated macrophage-like phenotype,which promotes tumor metastasis in vitro and in vivo.

Effects of Alexithymia to Stigma of Patients with Lymphedema

BACKGROUND: Secondary lymphedema is one of the common complications after malignant tumor surgery. It is a chronic and complex disease. Once lymphedema occurs, there will be discomfort such as limb swelling, pain, numbness and tension, which will eventually lead to changes in the appearance of the affected limb and will seriously affect the quality of life and require lifelong treatment and psychosocial support. This study investigated the current situation of stigma and alexithymia in patients with lymphedema, and discussed the impact of alexithymia on stigma in patients with lymphedema. AIMS: To understand the current situation of stigma and alexithymia in patients with lymphedema, and to analyze the influence of alexithymia on stigma. METHODS: 195 patients with lymphedema in a hospital were selected by convenient sampling. General information questionnaire, Toronto Alexithymia Scale and social impact scale were used to investigate respectively, to study the general situation, stigma and alexithymia of the respondents. RESULTS: The results showed that the total score of stigma in 195 patients with lymphedema was (60.36 ± 11.08), and the total score of alexithymia was (56.53 ± 8.43). Multiple linear regression analysis showed that alexithymia and family relationship were the influencing factors of stigma in patients with lymphedema. CONCLUSIONS: The patients with lymphedema have obvious stigma, and alexithymia and family relationship are the influencing factors.

Management of lymphedema is really a matter in patients with breast cancer

Lymphedema is a prevalent complication affecting patients with breast cancer,greatly impacting their quality of life.This editorial describes diagnostic methods and therapeutic interventions for managing lymphedema in patients with breast cancer.Diagnosis relies on clinical evaluation and objective measures,including arm circumference and volumetric assessments,along with lymphoscintigraphy and ultrasonic measurements.Treatment primarily involves complex decongestive physical therapy,comprising manual lymphatic drainage,compression therapy,exercise,and meticulous skin care.These interventions aim to reduce swelling,alleviate discomfort,and prevent further complications.Additionally,lifestyle modifications such as avoiding extreme temperatures and maintaining proper hygiene are essential.Flavonoids can be used for drug therapy.Despite its prevalence,lymphedema often receives inadequate attention in clinical practice,emphasizing the importance of raising awareness and enhancing medical services for affected individuals.Clinicians play a pivotal role in educating patients about preventive measures and ensuring timely intervention.Overall,a comprehensive approach encompassing early diagnosis,multidisciplinary management,and patient education is essential to mitigate the burden of lymphedema in patients with breast cancer and improve their overall well-being.

Tuberous sclerosis complex combined with primary lymphedema:A case report

BACKGROUND Tuberous sclerosis complex(TSC)and primary lymphedema(PLE)are both rare diseases,and it is even rarer for both to occur in the same patient.In this work,we have provided a detailed description of a patient's clinical presentation,imaging findings,and treatment.And a retrospective analysis was conducted on 14 published relevant case reports.CASE SUMMARY A 16-year-old male came to our hospital for treatment due to right lower limb swelling.This swelling is already present from birth.The patient’s memory had been progressively declining.Seizures had occurred 1 year prior at an unknown frequency.The patient was diagnosed with TSC combined with PLE through multimodal imaging examination:Computed tomography,magnetic resonance imaging,and lymphoscintigraphy.The patient underwent liposuction.The swelling of the patient's right lower limb significantly improved after surgery.Epilepsy did not occur.after taking antiepileptic drugs and sirolimus.CONCLUSION TSC with PLE is a rare and systemic disease.Imaging can detect lesions of this disease,which are important for diagnosis and treatment.

Vascularized lymph node transfer using axilla as recipient site restores lymphatic flow in upper limb lymphedema:Evidence from magnetic resonance lymphangiography

Background:Lymphedema is a debilitating condition that frequently occurs after breast cancer treatment.Vas-cularized lymph node transfer(VLNT)is a promising approach to reduce lymphedema.This study used magnetic resonance lymphangiography(MRL)to assess lymphatic reconnections post-VLNT in patients with breast cancer-related lymphedema(BCRL).Methods:The clinical records of six female patients with unilateral upper limb BCRL who underwent VLNT(4 cases)or VLNT combined with breast reconstruction(2 cases)were retrospectively reviewed.All patients were examined using MRL preoperatively and at the 1-year follow-up.The morphological characteristics of the lymphatic network,dermal backflow patterns,and architecture of the lymph nodes were evaluated.Clinical outcomes,patient satisfaction,and complications were assessed.Results:At the 1-year follow-up,reduction in tissue edema and limb circumference was achieved in all six patients.In MRL,the implanted lymph nodes in the axillary region of the affected upper arm were enhanced and visualized in all six patients.Reconnected lymphatic vessels in the subcutaneous tissue associated with the implanted lymph nodes were observed in four patients.Decreased dermal backflow and lymphatic vessel dilation of the affected limbs were observed in all six patients.No disruption of the lymph flow in the donor area was detected.Conclusion:This is the first study to provide direct imaging evidence for the reconnection of afferent lymphatic channels between implanted lymph nodes and the recipient lymphatic system in patients with BCRL.Overall,our study demonstrates the mechanism and efficacy of VLNT in reducing lymphedema.

Lymphovenous anastomosis and complex decongestive therapy for severe deformed lymphedema with recurrent infection:A case report

BACKGROUND Lower extremity lymphedema is a common complication following treatment for gynecological malignancies.Its incidence rate can reach up to 70%,affecting~20 million people worldwide.However,specialized treatment centers are scarce,and there is a lack of consensus on treatment approaches.Furthermore,there are even fewer reports on the systematic and effective treatment of severe lymphedema with malformations.Effective management of this condition remains a significant challenge for clinicians.CASE SUMMARY A 40-year-old woman developed bilateral leg swelling 6 years after receiving treatment for endometrial cancer.Since August 2018,she experienced>30 episodes of lymphangitis.Upon presentation,she exhibited bilateral leg swelling and deformation,with four large swellings in the posterior thigh that impeded movement,and pain in the limbs.Skin manifestations included lichenoid lesions and features of deep sclerosis.Radionuclide lymphoscintigraphy confirmed the diagnosis of lower limb lymphedema.After 6 mo of complex decongestive therapy(CDT)and three lymphaticovenous anastomosis(LVA)treatments,the patient lost 49 kg in weight.She also experienced a maximum circumference reduction of 35.2 cm in the left lower limb and 37.5 cm in the right lower limb.The leg pain disappeared,her swelling significantly decreased,and she regained the ability to walk,cycle,and run normally.CONCLUSION The combined application of CDT and LVA therapy demonstrates significant positive effects in the treatment of severe,deformed stage III lymphedema.

Preprocessing and Efficacy Analysis of Comprehensive Anti-Inflammatory Treatment for Lymphedema in Patients with Irritating Contact Dermatitis

Objective: To explore the pre-treatment and efficacy analysis of comprehensive anti-inflammatory treatment for lymphedema in patients with irritating contact dermatitis. Method: Convenience sampling method was used to observe the skin of 160 patients with upper limb lymphedema admitted to the lymphedema outpatient department of our hospital. They were divided into an observation group (80 cases) and a control group (80 cases), and both groups received a course of comprehensive anti-inflammatory treatment (20 treatments). The control group received routine skin care;On the basis of the control group, the observation group received pre-treatment of the affected limb skin: Laofuzi herbal ointment was applied externally to the prone areas of irritating contact dermatitis (such as the upper arm, inner forearm, and cubital fossa). Result: The incidence of irritating contact dermatitis in the observation group was significantly lower than that in the control group (P 0.05). Patients in the observation group felt significantly better in terms of comfort, skin moisture, and itching relief after being wrapped with low elasticity bandages than those in the control group (P Conclusion: Preventive treatment can effectively reduce the incidence of irritating contact dermatitis, prolong the time of stress treatment, thereby increasing efficacy and improving patient compliance.

Tumor-associated macrophages regulate gastric cancer cell invasion and metastasis through TGFβ2/NF-κB/Kindlin-2 axis

Objective: Recent studies have shown that tumor-associated macrophages(TAMs) play an important role in cancer invasion and metastasis. Our previous studies have reported that TAMs promote the invasion and metastasis of gastric cancer(GC) cells through the Kindlin-2 pathway. However, the mechanism needs to be clarified.Methods: THP-1 monocytes were induced by PMA/interleukin(IL)-4/IL-13 to establish an efficient TAM model in vitro and M2 macrophages were isolated via flow cytometry. A dual luciferase reporter system and chromatin immunoprecipitation(Ch IP) assay were used to investigate the mechanism of transforming growth factor β2(TGFβ2) regulating Kindlin-2 expression. Immunohistochemistry was used to study the relationships among TAM infiltration in human GC tissues, Kindlin-2 protein expression, clinicopathological parameters and prognosis in human GC tissues. A nude mouse oncogenesis model was used to verify the invasion and metastasis mechanisms in vivo.Results: We found that Kindlin-2 expression was upregulated at both m RNA and protein levels in GC cells cocultured with TAMs, associated with higher invasion rate. Kindlin-2 knockdown reduced the invasion rate of GC cells under coculture condition. TGFβ2 secreted by TAMs regulated the expression of Kindlin-2 through the transcription factor NF-кB. TAMs thus participated in the progression of GC through the TGFβ2/NF-κB/Kindlin-2 axis. Kindlin-2 expression and TAM infiltration were significantly positively correlated with TNM stage, and patients with high Kindlin-2 expression had significantly poorer overall survival than patients with low Kindlin-2 expression. Furthermore, Kindlin-2 promoted the invasion of GC cells in vivo.Conclusions: This study elucidates the mechanism of TAMs participating in GC cell invasion and metastasis through the TGFβ2/NF-κB/Kindlin-2 axis, providing a possibility for new treatment options and approaches.

Epigenetic modification regulates both expression of tumor-associated genes and cell cycle progressing in human colon cancer cell lines: Colo-320 and SW1116

The aim of this study is to assess the effects of DNA methylation and historic acetylation, alone or in combination, on the expression of several tumor-associated genes and cell cycle progression in two established human colon cancer cell lines: Colo-320 and SW1116. Treatments with 5-aza-2'-deoxycytidine (5-aza-dC) and trichostatin A, alone or in combination, were applied respectively. The methylation status of the CDKN2A promoter was determined by methyla-tion-specific PCR, and the acetylated status of the histones associated with the p21WAF1 and CDKN2A genes was examined by chromatin immunoprecipitation. The expression of the CDKN2A, p21WAF1, p53, p73, APC, c-myc, c-Ki-ras and survivin genes was detected by real-time RT-PCR and RT-PCR. The cell cycle profile was established by flow cytometry. We found that along with the demethylation of the CDKN2A gene promoter in both cell lines induced by 5-aza-dC alone or in combination with TSA, the expression of both CDKN2A and APC genes increased. The treatment of TSA or sodium butyrate up-regulated the transcription of p21WAF1 significantly by inducing the acetylation of histones H4 and H3, but failed to alter the acetylation level of CDKN2A-associated histones. No changes in transcription of p53, p73, c-myc, c-Ki-ras and survivin genes were observed. In addition, TSA or sodium butyrate was shown to arrest cells at the G1 phase. However, 5-aza-dC was not able to affect the cell cycle progression. In conclusion, regulation by epigenetic modification of the transcription of tumor-associated genes and the cell cycle progression in both human colon cancer cell lines Colo-320 and SW1116 is gene-specific.

Colorectal cancer vaccines: Tumor-associated antigens vs neoantigens

Therapeutic options for the treatment of colorectal cancer(CRC) are diverse but still not always satisfying. Recent success of immune checkpoint inhibition treatment for the subgroup of CRC patients suffering from hypermutated tumors suggests a permanent role of immune therapy in the clinical management of CRC. Substantial improvement in treatment outcome could be achieved by development of efficient patient-individual CRC vaccination strategies. This mini-review summarizes the current knowledge on the two general classes of targets: tumor-associated antigens(TAAs) and tumorspecific antigens. TAAs like carcinoembryonic antigen and melanoma associated antigen are present in and shared by a subgroup of patients and a variety of clinical studies examined the efficacy of different TAA-derived peptide vaccines. Combinations of several TAAs as the next step and the development of personalized TAA-based peptide vaccines are discussed. Improvements of peptidebased vaccines achievable by adjuvants and immunestimulatory chemotherapeutics are highlighted. Finally, we sum up clinical studies using tumor-specific antigens-in CRC almost exclusively neoantigens-which revealed promising results; particularly no severe adverse events were reported so far. Critical progress for clinical outcomes can be expected by individualizing neoantigen-based peptide vaccines and combining them with immunestimulatory chemotherapeutics and immune checkpoint inhibitors. In light of these data and latest developments, truly personalized neoantigen-based peptide vaccines can be expected to fulfill modern precision medicine's requirements and will manifest as treatment pillar for routine clinical management of CRC.

Targeting and exploitation of tumor-associated neutrophils to enhance immunotherapy and drug delivery for cancer treatment

Neutrophils,the most abundant leukocytes in human blood,are essential fighter immune cells against microbial infection.Based on the finding that neutrophils can either restrict or promote cancer progression,tumor-associated neutrophils(TAN)are classified into anti-tumor N1 and pro-tumor N2 subsets.One of the major mechanisms underlying the tumor-promoting function of N2-TANs is suppression of adaptive immune cells,in particular,cytotoxic T lymphocytes.Currently,no established methodologies are available that can unequivocally distinguish immunosuppressive TANs and granulocytic/polymorphonuclear myeloid-derived suppressor cells(G/PMN-MDSC).In view of the critical role of PMN-MDSCs in immune evasion and resistance to cancer immunotherapy,as established from data obtained with diverse cancer models,therapeutic strategies targeting these cells have been actively developed to enhance the efficacy of immunotherapy.Here,we have reviewed the available literature on strategies targeting PMN-MDSCs and summarized the findings into four categories:(1)depletion of existing PMN-MDSCs,(2)blockade of the development of PMNMDSCs,(3)blockade of PMN-MDSC recruitment,(4)inhibition of immunosuppressive function.Owing to their high mobility to inflamed organs and ability to trespass the blood-brain barrier,neutrophils are outstanding candidate carriers in nanoparticle-based therapies.Another attractive application of neutrophils in cancer therapy is the use of neutrophil membrane-derived nanovesicles as a surrogate of extracellular vesicles for more efficient and scalable drug delivery.In the second part of the review,we have highlighted recent advances in the field of neutrophil-based cancer drug delivery.Overall,we believe that neutrophil-based therapeutics are a rapidly growing area of cancer therapy with significant potential benefits.

Promotion of Sema4D expression by tumor-associated macrophages: Significance in gastric carcinoma

AIM To study the role of semaphorin 4 D(Sema4 D) expression promoted by tumor-associated macrophages(TAMs) in gastric carcinoma cells and its clinical significance in the invasion and metastasis of gastric carcinoma.METHODS CD68 and Sema4 D expression was analyzed in gastric carcinoma and adjacent normal tissues from 290 patients using the immunohistochemical streptavidinperoxidase method, and their relationships with clinicopathological features were evaluated. Human M2 macrophages were induced in vitro and co-cultured in non-contact with gastric carcinoma SGC-7901 cells. Changes in the secretory Sema4 D level in the SGC-7901 cell supernatant were measured using an enzymelinked immunosorbent assay. The effects of TAMs on SGC-7901 cell invasion and migration were assessed with invasion and migration assays, respectively.RESULTS CD68 and Sema4 D protein expression was significantly higher in gastric carcinoma tissues than in adjacent normal tissues(71.7% vs 33.8% and 74.5% vs 42.8%, respectively; P < 0.01). CD68 and Sema4 D protein expression was significantly associated with histological differentiation, TNM stage, and lymph node metastasis(P < 0.05), and their expression levels were positively correlated with one another(r = 0.467, P < 0.01). In the in vitro experiment, secretory Sema4 D protein expression was significantly increased in the supernatant of SGC-7901 cells co-cultured with TAMs compared with the blank control(1224.13 ± 29.43 vs 637.15 ± 33.84, P < 0.01). Cell invasion and metastasis were enhanced in the Transwell invasion and migration assays(P < 0.01).CONCLUSION TAMs promote the invasion and metastasis of gastric carcinoma cells possibly through upregulated secretory Sema4 D protein expression. Combined detection of TAM markers, CD68 and Sema4 D, in gastric carcinoma tissue shows potential to predict the trend of gastric carcinoma progression.