Tumor microenvironment: driving forces and potential therapeutic targets for breast cancer metastasis

Distant metastasis to specific target organs is responsible for over 90%of breast cancer?related deaths,but the underlying molecular mechanism is unclear.Mounting evidence suggests that the interplay between breast cancer cells and the target organ microenvironment is the key determinant of organ?specific metastasis of this lethal disease.Here,we highlight new findings and concepts concerning the emerging role of the tumor microenvironment in breast cancer metastasis;we also discuss potential therapeutic intervention strategies aimed at targeting compo?nents of the tumor microenvironment.

Research progress on the role of tumor microenvironment in tumor metastasis

Tumor metastasis is the basic feature and important sign of malignant tumors,and the main cause of death for most cancer patients.The tumor microenvironment is closely related to tumor metastasis and a deep understanding of the relationship between tumor microenvironment and tumor metastasis has positive guiding significance for the prevention and treatment of tumors.The occurrence,development and metastasis of tumors involve a series of complex biological processes.In the process of tumor metastasis,the tumor microenvironment cooperates with tumor cells.Tumor microenvironment is composed of cellular components,physical components and biochemical components,and it participates in important biological processes such as tumor growth,invasion,metastasis,neovascularization,immune escape,and tumor drug resistance.The study of tumor microenvironment can help us better understand the biological behavior of tumor and control the occurrence,development and metastasis of tumor.

Role of cancer stem cell ecosystem on breast cancer metastasis and related mouse models

Breast cancer metastasis is responsible for most breast cancer-related deaths and is influenced by many factors within the tumor ecosystem,including tumor cells and microenvironment.Breast cancer stem cells(BCSCs)constitute a small population of cancer cells with unique characteristics,including their capacity for self-renewal and differentiation.Studies have shown that BCSCs not only drive tumorigenesis but also play a crucial role in promoting metastasis in breast cancer.The tumor microenvironment(TME),composed of stromal cells,immune cells,blood vessel cells,fibroblasts,and microbes in proximity to cancer cells,is increasingly recognized for its crosstalk with BCSCs and role in BCSC survival,growth,and dissemination,thereby influencing metastatic ability.Hence,a thorough understanding of BCSCs and the TME is critical for unraveling the mechanisms underlying breast cancer metastasis.In this review,we summarize current knowledge on the roles of BCSCs and the TME in breast cancer metastasis,as well as the underlying regulatory mechanisms.Furthermore,we provide an overview of relevant mouse models used to study breast cancer metastasis,as well as treatment strategies and clinical trials addressing BCSC-TME interactions during metastasis.Overall,this study provides valuable insights for the development of effective therapeutic strategies to reduce breast cancer metastasis.

Effect of colorectal cancer stem cells on the development and metastasis of 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.

Impact of immunotherapy on liver metastasis

This editorial discusses the article“Analysis of the impact of immunotherapy efficacy and safety in patients with gastric cancer and liver metastasis”published in the latest edition of the World Journal of Gastrointestinal Surgery.Immunotherapy has achieved outstanding success in tumor treatment.However,the presence of liver metastasis(LM)restrains the efficacy of immunotherapy in various tumors,including lung cancer,colorectal cancer,renal cell carcinoma,melanoma,and gastric cancer.A decrease in CD8+T cells and nature killer cells,along with an increase in macrophages and regulatory T cells,was observed in the microenvironment of LM,leading to immunotherapy resistance.More studies are necessary to determine the best strategy for enhancing the effectiveness of immunotherapy in patients with LM.

Immunotherapy in gastric cancer with liver metastasis:Challenges and opportunities

In this editorial,we review the article by Liu et al published in the World Journal of Gastrointestinal Surgery investigating the efficacy and safety of immunotherapy in patients with gastric cancer(GC)and liver metastasis.GC,the fifth most com-monly diagnosed malignancy worldwide,presents a significant challenge due to its multifactorial etiology and a grim prognosis for unresectable or recurrent cases.The advent of immune checkpoint inhibitors(ICIs)has revolutionized oncology;yet liver metastasis has been associated with reduced response rates,progression-free survival,and overall survival in various malignancies.The Che-ckMate-649 and KEYNOTE-859 trials demonstrated promising results with ICIs in advanced GC,particularly in patients with liver metastasis.However,a meta-analysis of liver metastatic solid tumors revealed worse outcomes with ICIs,high-lighting the need for further investigation.While combined therapies,including ICIs with local treatments,show promise in improving outcomes,the nuanced landscape of ICIs in liver metastatic GC necessitates continued research for robust conclusions.The current contradictions in the literature underscore the impor-tance of cautious interpretation and the exploration of tailored approaches to enhance clinical efficacy in this challenging patient population.

Mutant p53 increases exosome-mediated transfer of mi R-21-3p and mi R-769-3p to promote pulmonary metastasis

Objective: Tumor metastasis is a complex, multistep process that depends on tumor cells and their communication with the tumor microenvironment. A p53 gain-of-function mutant has been shown to enhance the tumorigenesis, invasion, and metastasis abilities of tumor cells. This study aimed to investigate the roles of p53 R273 H mutation in the tumor microenvironment.Methods: The in vitro and in vivo effects of the p53 R273 H mutant on the invasion and metastasis of HCT116 cells were investigated. Exosomes from wild-type and HCT116-TP53(R273 H) cells were cocultured with mouse embryonic fibroblasts(MEFs). The roles of differentially expressed exosomal micro RNAs identified by microarray analysis were investigated. The functions of the p53 R273 H mutant in tumor cells were also investigated via gene expression microarray and quantitative polymerase chain reaction(q PCR) analyses.Results: Introducing p53 R273 H mutant into HCT116 cells significantly potentiated pulmonary metastasis in vivo. In the presence of exosomes derived from HCT116-TP53(R273 H) cells, the exosomes were taken up by MEFs and became activated. Microarray analysis showed that the p53 R273 H mutation increased the exosomal levels of mi R-21-3 p and mi R-769-3 p. Intriguingly, in clinical samples, mi R-21-3 p and mi R-769-3 p levels were significantly higher in patients with a p53 mutation than in those without this mutation. Furthermore, both mi R-21-3 p and mi R-769-3 p activated fibroblasts and exerted a synergistic effect via their target genes on the transforming growth factor-β(TGF-β)/Smad signaling pathway. The activated fibroblasts excreted cytokine TGF-β and may have reciprocally induced cancer cells to undergo epithelial-mesenchymal transition(EMT). Indeed, HCT116-TP53(R273 H) cells showed increased expression of ZEB1 and SNAI2 and decreased transcription of several cell adhesion molecules.Conclusions: The mutant p53-exosomal mi R-21-3 p/mi R-769-3 p-fibroblast-cytokine circuit appears to be responsible for communication between tumor and stromal cells, with exosomal mi RNAs acting as a bridge. mi R-21-3 p and mi R-769-3 p are potential predictive markers of pulmonary metastasis and candidate targets for therapeutic interventions.

Role of platelets and breast cancer stem cells in metastasis

The high mortality rate of breast cancer is mainly caused by the metastatic ability of cancer cells,resistance to chemotherapy and radiotherapy,and tumor regression capacity.In recent years,it has been shown that the presence of breast cancer stem cells is closely associated with the migration and metastatic ability of cancer cells,as well as with their resistance to chemotherapy and radiotherapy.The tumor microenvironment is one of the main molecular factors involved in cancer and metastatic processes development,in this sense it is interesting to study the role of platelets,one of the main communicator cells in the human body which are activated by the signals they receive from the microenvironment and can generate more than one response.Platelets can ingest and release RNA,proteins,cytokines and growth factors.After the platelets interact with the tumor microenvironment,they are called"tumor-educated platelets."Tumor-educated platelets transport material from the tumor microenvironment to sites adjacent to the tumor,thus helping to create microenvironments conducive for the development of primary and metastatic tumors.It has been observed that the clone capable of carrying out the metastatic process is a cancer cell with stem cell characteristics.Cancer stem cells go through a series of processes,including epithelial-mesenchymal transition,intravasation into blood vessels,movement through blood vessels,extravasation at the site of the establishment of a metastatic focus,and site colonization.Tumor-educated platelets support all these processes.

Curcumin Inhibits Prostate Cancer Bone Metastasis by Up-Regulating Bone Morphogenic Protein-7 <i>in Vivo</i>

A number of studies have focused on the beneficial properties of Curcumin (diferuloyl methane, used in South Asian cuisine and traditional medicine) such as the chemoprevention of cancer. Recent studies have also indicated that this material has significant benefits for the treatment of cancer and is currently undergoing several clinical trials. We have been interested in the application of this compound as a therapeutic agent for advanced prostate cancer, particularly the skeletal complications in this malignancy. Our earlier work indicated that this compound could inhibit the osteomimetic properties which occur in castration resistant prostate cancer cells, by interfering with the common denominators between these cancer cells and the bone cells in the metastatic tumor microenvironment, namely the osteoblasts and the osteoclast. We predicted that curcumin could break the vicious cycle of reciprocal stimulation that results in uncontrolled osteolysis in the bony matrix. In this work, we have evaluated the potential of this compound in inhibiting the bone metastasis of hormone refractory prostate cancer cells in an established animal model. Our results strongly suggest that curcumin modulates the TGF-βsignaling that occurs due to bone matrix degradation by up-regulating the metastasis inhibitory bone morphogenic protein-7 (BMP-7). This enhancement of BMP-7 in the context of TGF-β in the tumor microenvironment is shown to enhance the mesenchymal-to-epithelial transition. Most importantly, we show that as a result of BMP-7 up-regulation, a novel brown/beige adipogenic differentiation program is also up-regulated which plays a role in the inhibition of bone metastasis. Our results suggest that curcumin may subvert the TGF-β signaling to an alternative adipogenic differentiation program in addition to the previously established interference with the osteomimetic properties, thus inhibiting the bone metastatic processes in a chemopreventive as well as therapeutic setting.

Role of exosomes in metastasis and therapeutic resistance in esophageal cancer

Esophageal cancer(EC)has a high incidence and mortality rate and is emerging as one of the most common health problems globally.Owing to the lack of sensitive detection methods,uncontrollable rapid metastasis,and pervasive treatment resistance,EC is often diagnosed in advanced stages and is susceptible to local recurrence.Exosomes are important components of intercellular communication and the exosome-mediated crosstalk between the cancer and surrounding cells within the tumor microenvironment plays a crucial role in the metastasis,progression,and therapeutic resistance of EC.Considering the critical role of exosomes in tumor pathogenesis,this review focused on elucidating the impact of exosomes on EC metastasis and therapeutic resistance.Here,we summarized the relevant signaling pathways involved in these processes.In addition,we discussed the potential clinical applications of exosomes for the early diagnosis,prognosis,and treatment of EC.

Review of Premetastasis Niche Research Progress

In recent years, the field of premetastasis niche has attracted more and more attention from international scholars and has become a hot research direction. This article summarizes the current research on the role of the premetastasis niche, the components and formation mechanisms of the premetastasis niche, and the research on the significance of the premetastasis niche to the clinic. Effective cancer diagnosis and treatment strategies are important. A series of research advances in this field are of great significance for further elucidating the mechanism of tumor metastasis and designing more effective cancer diagnosis and treatment strategies.

Synaptophysin-like 2 expression correlates with lymph node metastasis and poor prognosis in colorectal cancer patients

BACKGROUND Colorectal cancer(CRC)is one of the most common and fatal cancers worldwide.Synaptophysin-like 2(SYPL2)is a neuroendocrine-related protein highly expressed in skeletal muscle and the tongue.The involvement of SYPL2 in CRC,including its level of expression and function,has not been evaluated.AIM To evaluate the correlations of SYPL2 expression with lymph node metastasis(LNM)and prognosis in patients with CRC.METHODS The levels of expression of SYPL2 in CRC and normal colorectal tissues were analyzed in multiple public and online databases.The associations between clinical variables and SYPL2 expression were evaluated statistically,and the associations between SYPL2 expression and prognosis in patients with CRC were analyzed using the Kaplan-Meier method and univariate/multivariate Cox regression analyses.SYPL2 expression was assessed in 20 paired CRC tissue and adjacent normal colorectal tissue samples obtained from Fuyang People’s Hospital,and the associations between SYPL2 expression and the clinical characteristics of these patients were investigated.Correlations between the levels of expression of SYPL2 and key targeted genes were determined by Pearson’s correlation analysis.The distribution of immune cells in these samples was calculated using the CIBERSORT algorithm.Gene set enrichment analysis(GSEA)was performed to evaluate the biofunction and pathways of SYPL2 in CRC.RESULTS SYPL2 expression was significantly lower in CRC tissue samples than in normal colorectal tissue samples(P<0.05).High SYPL2 levels in CRC tissues correlated significantly with LNM(P<0.05)and a poorer patient prognosis,including significantly shorter overall survival(OS)[hazard ratio(HR)=1.9,P<0.05]and disease-free survival(HR=1.6,P<0.05).High SYPL2 expression was an independent risk factor for OS in both univariate(HR=2.078,P=0.014)and multivariate(HR=1.754,P=0.018)Cox regression analyses.In addition,SYPL2 expression correlated significantly with the expression of KDR(P<0.0001,r=0.47)and the BRAFV600E mutation(P<0.05).Higher SYPL2 expression was associated with the enrichment of CD8 T-cells and M0 macrophages in the tumor microenvironment.GSEA revealed that SYPL2 was associated with the regulation of epithelial cell migration,vasculature development,pathways in cancer,and several vital tumor-related pathways.CONCLUSION SYPL2 expression was lower in CRC tissue than in normal colorectal tissue.Higher SYPL2 expression in CRC was significantly associated with LNM and poorer survival.

Understanding the function of the tumor microenvironment,and compounds from marine organisms for breast cancer therapy

The pathology and physiology of breast cancer(BC),including metastasis,and drug resistance,is driven by multiple signaling pathways in the tumor microenvironment(TME),which hamper antitumor immunity.Recently,long non-coding RNAs have been reported to mediate pathophysiological developments such as metastasis as well as immune suppression within the TME.Given the complex biology of BC,novel personalized therapeutic strategies that address its diverse pathophysiologies are needed to improve clinical outcomes.In this review,we describe the advances in the biology of breast neoplasia,including cellular and molecular biology,heterogeneity,and TME.We review the role of novel molecules such as long non-coding RNAs in the pathophysiology of BC.Finally,we provide an up-to-date overview of anticancer compounds extracted from marine microorganisms,crustaceans,and fishes and their synergistic effects in combination with other anticancer drugs.Marine compounds are a new discipline of research in BC and offer a wide range of anti-cancer effects that could be harnessed to target the various pathways involved in BC development,thus assisting current therapeutic regimens.

外泌体miRNA参与肿瘤化疗耐药的机制

背景:化疗作为癌症治疗的常见手段,前期具有一定的治疗效果,但随着化疗次数增加,肿瘤细胞对药物的抵抗性也逐渐增加,即化疗耐药性。目前化疗耐药性产生的主要机制包括化疗药物未能达到肿瘤部位,药物活性丧失导致药效下降,肿瘤细胞通过重塑代谢功能、基因表型和微环境逃避药物攻击等,但具体机制还有待深入探讨。目的:归纳并总结不同肿瘤中外泌体miRNA参与耐药的机制,提出潜在靶点。方法:以“hematological malignancies,liver cancer,lung cancer,breast cancer,melanoma,colorectal cancer,drug resistance,exosomal miRNAs”为英文检索词,检索PubMed数据库。检索时间范围为2013年1月至2023年8月。通过阅读文题和摘要进行初步筛选,排除与此次研究内容相关性差或内容重复的文献,最后纳入60篇文献进行综述。结果与结论:(1)外泌体miRNA进入细胞间质和循环,通过发挥局部旁分泌或远端效应,参与不同肿瘤生物进程的形成和发展,包括肿瘤微环境重塑、血管生成和耐药性产生;(2)外泌体miRNA可以透过细胞膜进入另一个细胞的胞浆内,通过传递miRNA启动或抑制受体细胞中的信号通路,在化疗过程中维持细胞存活、增殖和转移能力,从而导致耐药产生;(3)目前已经鉴定出许多与化疗耐药有关的外泌体miRNA,并将其作为常见肿瘤治疗靶点来开展研究;(4)虽然外泌体miRNA作为潜在的生物标志物和治疗靶点具有很大的前景,但仍有一些研究缺陷需要解决:一是缺乏用于外泌体分离和表征的标准化方案,导致不同研究中使用的方法存在差异;二是虽然外泌体中miRNA的存在和丰度已被广泛研究,但其功能作用和作用机制尚不完全清楚,阐明外泌体miRNA调控的特定靶点和途径可以为它们的生物学意义和潜在的治疗应用提供有价值的见解。解决这些研究缺陷将有助于更全面了解外泌体miRNA及其在各个领域的潜在应用,包括诊断、治疗和个性化医疗。

Interactions between cancer cells and bone microenvironment promote bone metastasis in prostate cancer

Bone metastasis is the leading cause of death in prostate cancer patients,for which there is currently no effective treatment.Since the bone microenvironment plays an important role in this process,attentions have been directed to the interactions between cancer cells and the bone microenvironment,including osteoclasts,osteoblasts,and bone stromal cells.Here,we explained the mechanism of interactions between prostate cancer cells and metastasis-associated cells within the bone microenvironment and further discussed the recent advances in targeted therapy of prostate cancer bone metastasis.This review also summarized the effects of bone microenvironment on prostate cancer metastasis and the related mechanisms,and provides insights for future prostate cancer metastasis studies.

VEGFR2-targeted antibody fused with IFNamut regulates the tumor microenvironment of colorectal cancer and exhibits potent anti-tumor and anti-metastasis activity

Although interferonα(IFNα)and anti-angiogenesis antibodies have shown appropriate clinical benefit in the treatment of malignant cancer,they are deficient in clinical applications.Previously,we described an anti-vascular endothelial growth factor receptor 2(VEGFR2)-IFNαfusion protein named JZA01,which showed increased in vivo half-life and reduced side effects compared with IFNα,and it was more effective than the anti-VEGFR2 antibody against tumors.However,the affinity of the IFNv component of the fusion protein for its receptor-IFNAR1 was decreased.To address this problem,an IFNα-mutant fused with anti-VEGFR2 was designed to produce anti-VEGFR2-IFNamut,which was used to target VEGFR2 with enhanced anti-tumor and anti-metastasis efficacy.Anti-VEGFR2-IFNamut specifically inhibited proliferation of tumor cells and promoted apoptosis.In addition,antiVEGFR2-IFNαmut inhibited migration of colorectal cancer cells and invasion by regulating the PI3 K-AKT-GSK3β-snail signal pathway.Anti-VEGFR-2-IFNamut showed superior anti-tumor efficacy with improved tumor microenvironment(TME)by enhancing dendritic cell maturation,dendritic cell activity,and increasing tumor-infiltrating CD8+T cells.Thus,this study provides a novel approach for the treatment of metastatic colorectal cancer,and this design may become a new approach to cancer immunotherapy.

Cell cycle-related kinase reprograms the liver immune microenvironment to promote cancer metastasis

The liver is an immunologically tolerant organ and a common metastatic site of multiple cancer types.Although a role for cancer cell invasion programs has been well characterized,whether and how liver-intrinsic factors drive metastatic spread is incompletely understood.Here,we show that aberrantly activated hepatocyte-intrinsic cell cycle-related kinase(CCRK)signaling in chronic liver diseases is critical for cancer metastasis by reprogramming an immunosuppressive microenvironment.Using an inducible liverspecific transgenic model,we found that CCRK overexpression dramatically increased both B16F10 melanoma and MC38 colorectal cancer(CRC)metastasis to the liver,which was highly infiltrated by polymorphonuclear-myeloid-derived suppressor cells(PMNMDSCs)and lacking natural killer T(NKT)cells.Depletion of PMN-MDSCs in CCRK transgenic mice restored NKT cell levels and their interferon gamma production and reduced liver metastasis to 2.7% and 0.7%(metastatic tumor weights)in the melanoma and CRC models,respectively.Mechanistically,CCRK activated nuclear factor-kappa B(NF-κB)signaling to increase the PMN-MDSC trafficking chemokine C-X-C motif ligand 1(CXCL1),which was positively correlated with liver-infiltrating PMN-MDSC levels in CCRK transgenic mice.Accordingly,CRC liver metastasis patients exhibited hyperaaivation of hepatic CCRK/NF-κB/CXCL1 signaling,which was associated with accumulation of PMN-MDSCs and paucity of NKT cells compared to healthy liver transplantation donors.In summary,this study demonstrates that immunosuppressive reprogramming by hepatic CCRK signaling undermines antimetastatic immunosurveillance.Our findings offer new mechanistic insights and therapeutic targets for liver metastasis intervention.

Tumor microenvironment in lung cancer-derived brain metastasis

Brain metastasis(BM)is the leading cause of mortality in lung cancer patients.The process of BM(from initial primary tumor development,migration and intravasation,dissemination and survival in the bloodstream,extravasation,to colonization and growth to metastases)is a complex process for which few tumor cells complete the entire process.Recent research on BM of lung cancer has recently stressed the essential role of tumor microenvironment(TME)in assisting tumor cells in the completion of each BM step.This review summarizes recent studies regarding the effects of TME on tumor cells in the entire process of BM derived from lung cancer.The identification of vulnerable targets in the TME and their prospects to provide novel therapeutic opportunities are also discussed.

Folic acid-modified Exosome-PH20 enhances the efficiency of therapy via modulation of the tumor microenvironment and directly inhibits tumor cell metastasis

High accumulation of hyaluronan(HA)in the tumor microenvironment leads to an increase in the interstitial pressure and reduction perfusion of drugs.Furthermore,high molecular-weight(HMW)-HA suppresses M1 macrophage polarization,enhances M2 polarization,and induces immunosuppression.Hyaluronidase treatment have attempted to decrease the quantity of HA in tumors.However,hyaluronidase-driven HA degradation driven accelerates tumor cell metastasis,which is a major cause of mortality in cancer patients.Thus,we designed a novel exosome-based drug delivery system(DDS),named Exos-PH20-FA,using genetic engineering to express human hyaluronidase(PH20)and self-assembly techniques to modify the exosomes with folic acid(FA).Our results show that Exos-PH20-FA degraded HMW-HA to low-molecular-weight(LMW)-HA.Moreover,LMW-HA polarized macrophages to the M1 phenotype and reduced the number of relevant immunosuppressive immunocytes which changed the immune microenvironment from an immunosuppressive to immunosupportive phenotype.Furthermore,we demonstrated Exos-PH20-FA directly reduced hyaluronidase-induced metastasis of tumor cells.This tumor treatment also allowed an enhanced delivery of chemotherapy by tumor-targeting effect with FA modification.Our findings indicate that Exos-PH20-FA improves tumor treatment efficiency and reduces the side effects of hyaluronidase treatment,namely tumor cell metastasis.This all-in-one exosome-based HA targeting DDS maybe a promising treatment that yields more efficient and safer results.

miR-7/TGF-β2 axis sustains acidic tumor microenvironment-induced lung cancer metastasis

Acidosis,regardless of hypoxia involvement,is recognized as a chronic and harsh tumor microenvironment(TME)that educates malignant cells to thrive and metastasize.Although overwhelming evidence supports an acidic environment as a driver or ubiquitous hallmark of cancer progression,the unrevealed core mechanisms underlying the direct effect of acidification on tumorigenesis have hindered the discovery of novel therapeutic targets and clinical therapy.Here,chemical-induced and transgenic mouse models for colon,liver and lung cancer were established,respectively.miR-7 and TGF-β2 expressions were examined in clinical tissues(n=184).RNA-seq,miRNA-seq,proteomics,biosynthesis analyses and functional studies were performed to validate the mechanisms involved in the acidic TME-induced lung cancer metastasis.Our data show that lung cancer is sensitive to the increased acidification of TME,and acidic TME-induced lung cancer metastasis via inhibition of miR-7-5 p.TGF-β2 is a direct target of miR-7-5 p.The reduced expression of miR-7-5 p subsequently increases the expression of TGF-β2 which enhances the metastatic potential of the lung cancer.Indeed,overexpression of miR-7-5 p reduces the acidic p H-enhanced lung cancer metastasis.Furthermore,the human lung tumor samples also show a reduced miR-7-5 p expression but an elevated level of activated TGF-β2;the expressions of both miR-7-5 p and TGF-β2 are correlated with patients’survival.We are the first to identify the role of the miR-7/TGF-β2 axis in acidic p H-enhanced lung cancer metastasis.Our study not only delineates how acidification directly affects tumorigenesis,but also suggests miR-7 is a novel reliable biomarker for acidic TME and a novel therapeutic target for non-small cell lung cancer(NSCLC)treatment.Our study opens an avenue to explore the p H-sensitive subcellular components as novel therapeutic targets for cancer treatment.