ASIC3-activated key enzymes of de novo lipid synthesis supports lactate-driven EMT and the metastasis of colorectal cancer cells.

Acidic microenvironments is a cancer progression driver, unclear core mechanism hinders the discovery of new diagnostic or therapeutic targets. ASIC3 is an extracellular proton sensor and acid-sensitive, but its role in acidic tumor microenvironment of colorectal cancer is not reported. Functional analysis data show that colorectal cancer cells respond to specific concentration of lactate to accelerate invasion and metastasis, and ASIC3 is the main actor in this process. Mechanism reveal de novo lipid synthesis is a regulatory process of ASIC3, down-regulated ASIC3 increases and interacts with ACC1 and SCD1, which are key enzymes in de novo lipid synthesis pathway, this interaction results in increased unsaturated fatty acids, which in turn induce EMT to promote metastasis, and overexpression of ASIC3 reduces acidic TME-enhanced colorectal cancer metastasis. Clinical samples of colorectal cancer also exhibit decreased ASIC3 expression, and low ASIC3 expression is associated with metastasis and stage of colorectal cancer. This study is the first to identify the role of the ASIC3-ACC1/SCD1 axis in acid-enhanced colorectal cancer metastasis. The expression pattern of ASIC3 in colorectal cancer differs significantly from that in other types of cancers, ASIC3 may serve as a novel and reliable marker for acidic microenvironmental in colorectal cancer, and potentially a therapeutic target.

Sulforaphane reverses the enhanced NSCLC metastasis by regulating the miR-7-5p/c-Myc/LDHA axis in the acidic tumor microenvironment.

BACKGROUND: The presence of distant metastasis at the time of initial diagnosis is a prevalent issue in non-small cell lung cancer (NSCLC), affecting around 30-40 % of the patients. Acidic tumor microenvironment (TME) provides favorable conditions that increase the invasiveness and aggressiveness of NSCLC. The activity of the glycolytic enzyme lactate dehydrogenase (LDHA) increases intracellular lactate accumulation, which creates an acidic TME. However, it is not yet known whether LDHA is involved in enhancing the metastatic potential of NSCLC and if LDHA is a druggable therapeutic target for NSCLC. PURPOSE: We aimed to investigate the molecular mechanisms underlying the enhanced NSCLC metastasis in acidic TME, and to explore whether sulforaphane (SFN), an active compound in Raphani Semen, can serve as a LDHA inhibitor to inhibit NSCLC metastasis in the acidic TME. METHODS: To mimic the acidic TME, NSCLC cells were cultured in acidic medium (pH 6.6), normal medium (pH 7.4) served as control. Western blotting, bioinformatic analysis, luciferase assay and rescue experiments were used to explore the mechanism and investigate the anti-metastatic effect of SFN both in vitro and in vivo. RESULTS: Acidic environment increases the expression of LDHA which in turn increases the production of lactic acid that contributes to the acidity of TME. Interestingly, elevated LDHA expression results from increased c-Myc expression, which transactivates LDHA. c-Myc expression is directly regulated by miR-7-5p. In vitro study shows that overexpression of miR-7-5p reverses the acidic pH-enhanced c-Myc and LDHA expressions and also abolishes the enhanced NSCLC cell migration. More importantly, SFN significantly inhibits NSCLC growth and metastasis by reducing lactate production via the miR-7-5p/c-Myc/LDHA axis. Besides, it also regulates the expressions of monocarboxylate transporter 1 (MCT1) and MCT4 that transport lactate across cell membrane. CONCLUSIONS: The miR-7-5p/c-Myc/LDHA axis is involved in the enhanced NSCLC metastasis in the acidic TME. SFN, a novel LDHA inhibitor, reduces lactate production by targeting the miR-7-5p/c-Myc/LDHA axis, and hence inhibits NSCLC metastasis. Our findings not only delineate a novel mechanism, but also support the clinical translation of SFN as a novel therapeutic agent for treating metastatic NSCLC.

Acidity-targeting transition-aided universal chimeric antigen receptor T-cell (ATT-CAR-T) therapy for the treatment of solid tumors.

The use of CAR-T cells in treating solid tumors frequently faces significant challenges, mainly due to the heterogeneity of tumor antigens. This study assessed the efficacy of an acidity-targeting transition-aided universal chimeric antigen receptor T (ATT-CAR-T) cell strategy, which is facilitated by an acidity-targeted transition. Specifically, the EGFRvIII peptide was attached to the N-terminus of a pH-low insertion peptide. Triggered by the acidic conditions of the tumor microenvironment, this peptide alters its structure and selectively integrates into the membrane of solid tumor cells. The acidity-targeted transition component effectively relocated the EGFRvIII peptide across various tumor cell membranes; thus, allowing the direct destruction of these cells by EGFRvIII-specific CAR-T cells. This method was efficient even when endogenous antigens were absent. In vivo tests showed marked antigen modification within the acidic tumor microenvironment using this component. Integrating this component with CAR-T cell therapy showed high effectiveness in combating solid tumors. These results highlight the capability of ATT-CAR-T cell therapy to address the challenges presented by tumor heterogeneity and expand the utility of CAR-T cell therapy in the treatment of solid tumors.

Proton-sensing ion channels, GPCRs and calcium signaling regulated by them: implications for cancer.

Extracellular acidification of tumors is common. Through proton-sensing ion channels or proton-sensing G protein-coupled receptors (GPCRs), tumor cells sense extracellular acidification to stimulate a variety of intracellular signaling pathways including the calcium signaling, which consequently exerts global impacts on tumor cells. Proton-sensing ion channels, and proton-sensing GPCRs have natural advantages as drug targets of anticancer therapy. However, they and the calcium signaling regulated by them attracted limited attention as potential targets of anticancer drugs. In the present review, we discuss the progress in studies on proton-sensing ion channels, and proton-sensing GPCRs, especially emphasizing the effects of calcium signaling activated by them on the characteristics of tumors, including proliferation, migration, invasion, metastasis, drug resistance, angiogenesis. In addition, we review the drugs targeting proton-sensing channels or GPCRs that are currently in clinical trials, as well as the relevant potential drugs for cancer treatments, and discuss their future prospects. The present review aims to elucidate the important role of proton-sensing ion channels, GPCRs and calcium signaling regulated by them in cancer initiation and development. This review will promote the development of drugs targeting proton-sensing channels or GPCRs for cancer treatments, effectively taking their unique advantage as anti-cancer drug targets.

Polyphenol nanocomplex modulates lactate metabolic reprogramming and elicits immune responses to enhance cancer therapeutic effect.

Cancer lactate metabolic reprogramming induces an elevated level of extracellular lactate and H+, leading to an acidic immunosuppressive tumor microenvironment (TEM). High lactic acid level may affect the metabolic programs of various cells that comprise an antitumor immune response, therefore, restricting immune-mediated tumor destruction, and leading to therapeutic resistance and unsatisfactory prognosis. Here, we report a metal-phenolic coordination-based nanocomplex loaded with a natural polyphenol galloflavin, which inhibits the function of lactate dehydrogenase, reducing the production of lactic acid, and alleviating the acidic immunosuppressive TME. Besides, the co-entrapped natural polyphenol carnosic acid and the synthetic PEG-Ce6 polyphenol derivative (serving as a photosensitizer) could induce immunogenic cancer cell death upon laser irradiation, which further activates immune system and promotes immune cell recruitment and infiltration in tumor tissues. We demonstrated that this nanocomplex-based combinational therapy could reshape the TME and elicit immune responses in a murine breast cancer model, which provides a promising strategy to enhance the therapeutic efficiency of drug-resistant breast cancer.

Uptake Pathway of Styrene Maleic Acid Copolymer-Coated Lipid Emulsions Under Acidic Tumor Microenvironment.

The purpose of this study was to elucidate and compare styrene maleic acid copolymer (SMA)-coated lipid emulsions (SMA emulsions) uptake pathway in vascular endothelial cells and surrounding cancer cells under not only neutral but also acidic pH, which is often observed in tumor microenvironment. DiI-labeled SMA emulsions were prepared using 1-palmitoyl-2-oleoyl-sn­glycero-3-phosphocholine and triolein. In murine melanoma B16-BL6 (B16) cells and human umbilical vein endothelial cells (HUVEC), DiI-labeled SMA emulsions uptake under near-neutral (pH 7.4) and acidic (pH 6.0) conditions was determined by fluorescent analysis. SMA emulsions were taken up more efficiently into HUVEC than B16 cells under acidic condition in a temperature-dependent manner. Uptake study using endocytosis inhibitors showed that SMA emulsions were taken up by macropinocytosis and clathrin-mediated endocytosis in B16 cells. In HUVEC, however, they were taken up by clathrin- and caveolae-independent, but dynamin-dependent pathway. SMA emulsions would be internalized efficiently into vascular endothelial cells as well as cancer cells under acidic microenvironment via different endocytosis pathways. SMA emulsions could be a promising drug delivery carrier for anti-angiogenic drugs.

Dual Tumor-Selective ß-Carboline-Based Fluorescent Probe for High-Contrast/Rapid Diagnosis of Clinical Tumor Tissues.

Given that precise/rapid intraoperative tumor margin identification is still challenging, novel fluorescent probes HY and HYM, based on acidic tumor microenvironment (TME) activation and organic anion transporting polypeptide (OATPs)-mediated selective uptake, were constructed and synthesized. Both of them possessed acidic pH-activatable and reversible fluorescence as well as large Stokes shift. Compared with HY, HYM had a higher (over 9-fold) enhancement in fluorescence with pH ranging from 7.6 to 4.0, and the fluorescence quantum yield of HYM (ΦF = 0.49) at pH = 4.0 was 8-fold stronger than that (ΦF = 0.06) at pH = 7.4. Mechanism research demonstrated that acidic TME-induced protonation of the pyridine N atom on ß-carbolines accounted for the pH-sensitive fluorescence by influencing the intramolecular charge transfer (ICT) effect. Furthermore, HYM selectively lit up cancer cells and tumor tissues not only by "off-on" fluorescence but also by OATPs (overexpressed on cancer cells)-mediated cancer cellular internalization, offering dual tumor selectivity for precise visualization of tumor mass and intraoperative guidance upon in situ spraying. Most importantly, HYM enabled rapid and high-contrast (tumor-to-normal tissue ratios > 6) human tumor margin identification in clinical tumor tissues by simple spraying within 6 min, being promising for aiding in clinical surgical resection.

Targeting the lactic acid metabolic pathway for antitumor therapy.

Lactic acid is one of the most abundant products of cellular metabolism and has historically been considered a cell-damaging metabolic product. However, as research has deepened, the beneficial effects of lactic acid on tumor cells and the tumor microenvironment have received increasing attention from the oncology community. Lactic acid can not only provide tumor cells with energy but also act as a messenger molecule that promotes tumor growth and progression and protects tumor cells from immune cells and killing by radiation and chemotherapy. Thus, the inhibition of tumor cell lactic acid metabolism has emerged as a novel antitumor treatment strategy that can also effectively enhance the efficacy of conventional antitumor therapies. In this review, we classify the currently available therapies targeting lactic acid metabolism and examine their prospects for clinical application.

Surface Functionalization of Gold Nanoparticles for Targeting the Tumor Microenvironment to Improve Antitumor Efficiency.

Gold nanoparticles (AuNPs) have undergone significant research for their use in the treatment of cancer. Numerous researchers have established their potent antitumor properties, which have greatly impacted the treatment of cancer. AuNPs have been used in four primary anticancer treatment modalities, namely radiation, photothermal therapy, photodynamic therapy, and chemotherapy. However, the ability of AuNPs to destroy cancer is lacking and can even harm healthy cells without the right direction to transport them to the tumor microenvironment. Consequently, a suitable targeting technique is needed. Based on the distinct features of the human tumor microenvironment, this review discusses four different targeting strategies that target the four key features of the tumor microenvironment, including abnormal vasculature, overexpression of specific receptors, an acidic microenvironment, and a hypoxic microenvironment, to direct surface-functionalized AuNPs to the tumor microenvironment and increase antitumor efficacies. In addition, some current completed or ongoing clinical trials of AuNPs will also be discussed below to further reinforce the concept of using AuNPs in anticancer therapy.

Acidic Growth Conditions Promote Epithelial-to-Mesenchymal Transition to Select More Aggressive PDAC Cell Phenotypes In Vitro.

Pancreatic Ductal Adenocarcinoma (PDAC) is characterized by an acidic microenvironment, which contributes to therapeutic failure. So far there is a lack of knowledge with respect to the role of the acidic microenvironment in the invasive process. This work aimed to study the phenotypic and genetic response of PDAC cells to acidic stress along the different stages of selection. To this end, we subjected the cells to short- and long-term acidic pressure and recovery to pHe 7.4. This treatment aimed at mimicking PDAC edges and consequent cancer cell escape from the tumor. The impact of acidosis was assessed for cell morphology, proliferation, adhesion, migration, invasion, and epithelial-mesenchymal transition (EMT) via functional in vitro assays and RNA sequencing. Our results indicate that short acidic treatment limits growth, adhesion, invasion, and viability of PDAC cells. As the acid treatment progresses, it selects cancer cells with enhanced migration and invasion abilities induced by EMT, potentiating their metastatic potential when re-exposed to pHe 7.4. The RNA-seq analysis of PANC-1 cells exposed to short-term acidosis and pHe-selected recovered to pHe 7.4 revealed distinct transcriptome rewiring. We describe an enrichment of genes relevant to proliferation, migration, EMT, and invasion in acid-selected cells. Our work clearly demonstrates that upon acidosis stress, PDAC cells acquire more invasive cell phenotypes by promoting EMT and thus paving the way for more aggressive cell phenotypes.

Acidic tumor microenvironment-activatable fluorescent diagnostic probe for the rapid identification and resection of human tumors via spraying.

A fluorescent diagnostic probe for real-time intraoperative image-guided tumor resection can significantly improve the efficiency and quality of oncological therapy, but their development is challenging. Herein, a novel fluorescent diagnostic probe called HLTC based on ß-carboline was designed and synthesized. HLTC was found to show a ∼10-fold enhancement of fluorescence quantum field with pH from 7.4 to 4.0, indicating its imaging potential in acid environment which is a typical hallmark of the tumor microenvironment (TME). Following fluorescence microscopy imaging showed HLTC could emit specific signals in cancer cells and sections, by both one-photon excitation and two-photon excitation. Importantly, HLTC enabled the precise and rapid delineation of both transplanted tumor and clinical tumor tissues within several minutes of simple topical spray. The tumor-to-background ratio (TBR) was up to 10.2 ± 1.0 at clinical liver cancer tissues and 9.9 ± 0.3 at clinical colon cancer tissues, allowing precise tumor margin identification and the effective guidance of surgical tumor resection. Furthermore, CCK8 assay, pharmacokinetic evaluation, blood analysis and H&E staining were performed, which verified high biocompatibility and biosafety of HLTC at working concentration. These results reveal the exciting potential of this small-molecule fluorescent diagnostic probe for real-time fluorescence-based navigation during surgical tumor resection.

Inhibition of IDH3α Enhanced the Efficacy of Chemoimmunotherapy by Regulating Acidic Tumor Microenvironments.

In recent years, chemoimmunotherapy has become effective in some advanced cancers, but its effect is still limited. Transcriptional upregulation of isocitrate dehydrogenase 3α (IDH3α) can promote tumor initiation and progression. However, it is not clear whether the aberrant expression of IDH3α is related to the efficacy of chemoimmunotherapy in cancers. Here, we found that IDH3α was elevated in uterine cervical cancer (UCC) and lung adenocarcinoma (LUAD) samples by using public databases. High expression of IDH3α could promote the epithelial-mesenchymal transition (EMT), alter the intracellular redox status, promote glycolysis, and induce an acidic microenvironments in cancer cells. Furthermore, we found that inhibition of IDH3α combined with chemoimmunotherapy (cisplatin and programmed cell death ligand 1 (PD-L1) antibodies) activated the cGAS-STING pathway, promoted CD8+ T cell infiltration, and decreased tumor growth in mouse models of cervical cancer. In conclusion, our data indicate that silencing IDH3α sensitizes tumors to chemoimmunotherapy by modulating the acidic microenvironment and activating the cGAS-STING pathway.

Rational design of pH-activated upconversion luminescent nanoprobes for bioimaging of tumor acidic microenvironment and the enhancement of photothermal therapy.

The development of effective and safe tumor photothermal therapeutic strategies has attracted considerable attention. Herein, we synthesized tumor microenvironment (TME)-activatable self-assembling organic nanotheranostics (NRhD-PEG-X NPs (X = 1, 2, 3, and 4)) for precise tumor targeting and upconversion image-guided photothermal therapy (PTT). The amphiphilic polymer NRhD-PEG-X consisted of upconversion luminescent probes (NRhD) modified with polyethylene glycol (PEG) of various lengths. The continuous external irradiation-free photothermal NRhD-PEG-4 NPs with pKa 6.70 displayed high sensitivity and selectivity to protons, resulting in the turn-on upconversion luminescence and enhanced photothermal properties in the acidic TME without asynchronous therapy and side effects. This nanotheranostic offers acidic activatability, tumor targetability, and PTT enhancement, thus allowing autofluorescence-free upconversion luminescent imaging-guided precision PTT. Our strategy affords a paradigm to develop activatable theranostic nanoplatforms for precision medicine. STATEMENT OF SIGNIFICANCE: As a hyperthermia-based treatment, activatable photothermal therapy (PTT) is highly significant in tumor treatment. Herein, we develop acidic tumor microenvironment-activatable nanotheranostics for upconversion luminescent imaging-guided diagnosis and precision tumor-targeted PTT. PEGylation of upconversion dyes not only could self-assemble to yield organic nanoparticles in water, but it could also significantly improve biocompatibility, stability, and circulation time and tune significantly the pKa value of nanoparticles. In an acidic tumor microenvironment, NRhD-PEG-4 NPs with pKa 6.70 show high sensitivity to release NRhDH+-PEG-4 NPs, which exhibit good upconversion luminescence and enhanced photothermal effect. Therefore, upconversion luminescence imaging-guided precision PTT has high potential to enhance cancer diagnostic and therapeutic efficiency.

miR-214-Enriched Extracellular Vesicles Released by Acid-Adapted Melanoma Cells Promote Inflammatory Macrophage-Dependent Tumor Trans-Endothelial Migration.

The understanding of the molecular mechanisms leading to melanoma dissemination is urgently needed in view of the identification of new targets and the development of innovative strategies to improve patients' outcomes. Within the complexity of tumor intercellular communications leading to metastatic dissemination, extracellular vesicles (EV) released by tumor cells are central players. Indeed, the ability to travel through the circulatory system conveying oncogenic bioactive molecules even at distant sites makes EV capable of modulating recipient cells to facilitate metastatic dissemination. The dynamic remodeling of the tumor microenvironment might influence, along with a number of other events, tumoral EV release. We observed that, in melanoma, extracellular acidosis increases the release of EV enriched in miR-214, an onco-miRNA involved in melanoma metastasis. Then, miR-214-enriched EV were found to induce a state of macrophage activation, leading to an overproduction of proinflammatory cytokines and nitric oxide. Such an inflammatory microenvironment was able to alter the endothelial cell permeability, thereby facilitating the trans-endothelial migration of melanoma cells, a crucial step in the metastatic cascade. The use of synthetic miR-214 inhibitors and miR-214 overexpression allowed us to demonstrate the key role of miR-214 in the EV-dependent induction of macrophage activation. Overall, our in vitro study reveals that the release of tumor miR-214-enriched EV, potentiated by adapting tumor cells to extracellular acidosis, drives a macrophage-dependent trans-endothelial migration of melanoma cells. This finding points to miR-214 as a potential new therapeutic target to prevent melanoma intravasation.

Oral administration of sodium bicarbonate can enhance the therapeutic outcome of Doxil® via neutralizing the acidic tumor microenvironment.

The pH of the tumor microenvironment in solid tumors is reported to be more acidic than that of normal tissues. The pH is controlled by over-expression of several transporters that are associated with the progression, angiogenesis, and metastasis of solid tumors. Antitumor effects of weak-base anticancer agents, such as doxorubicin (DXR), could be reduced in an acidic environment because of increases in the ionized form of the drug under these conditions, reducing its membrane penetrability. In our previous studies, we demonstrated that oral administration of sodium bicarbonate (NaHCO3) can neutralize the acidic tumor microenvironment and enhance the effects of small molecule anticancer drugs. However, it is not known whether or not increasing the tumor pH by oral administration of NaHCO3 leads to enhanced antitumor effects of lipidic nanoparticle formulations of weak-base anticancer drugs, such as Doxil®. In this study, we investigated the antitumor efficacy of Doxil® in combination with oral administration of NaHCO3 in a Colon26 tumor-bearing mouse model. NaHCO3 clearly enhanced the tumor-growth inhibitory effect of Doxil® without exacerbating any systemic side effects. In vitro studies indicated that high levels of DXR were internalized into cells at neutral pH. These studies demonstrate that the neutralization of acidic tumor microenvironment by an oral administration of NaHCO3 could be a promising approach to enhance the therapeutic outcomes of Doxil®.

PET Imaging of Acidic Tumor Environment With 89Zr-labeled pHLIP Probes.

Acidosis of the tumor microenvironment is a hallmark of tumor progression and has emerged as an essential biomarker for cancer diagnosis, prognosis, and evaluation of treatment response. A tool for quantitatively visualizing the acidic tumor environment could significantly advance our understanding of the behavior of aggressive tumors, improving patient management and outcomes. 89Zr-labeled pH-low insertion peptides (pHLIP) are a class of radiopharmaceutical imaging probes for the in vivo analysis of acidic tumor microenvironments via positron emission tomography (PET). Their unique structure allows them to sense and target acidic cancer cells. In contrast to traditional molecular imaging agents, pHLIP's mechanism of action is pH-dependent and does not rely on the presence of tumor-specific molecular markers. In this study, one promising acidity-imaging PET probe ([89Zr]Zr-DFO-Cys-Var3) was identified as a candidate for clinical translation.

Designing Lactate Dehydrogenase-Mimicking SnSe Nanosheets To Reprogram Tumor-Associated Macrophages for Potentiation of Photothermal Immunotherapy.

Rapid glycolysis of tumor cells produces excessive lactate to trigger acidification of the tumor microenvironment (TME), leading to the formation of immunosuppressive TME and tumor-associated macrophage (TAM) dysfunction. Therefore, reprogramming TAMs by depleting lactate with nanodrugs is expected to serve as an effective means of tumor-targeted immunotherapy. Herein, we report the use of lactic acid dehydrogenase (LDH)-mimicking SnSe nanosheets (SnSe NSs) loaded with a carbonic anhydrase IX (CAIX) inhibitor to reconstruct an acidic and immunosuppressive TME. As expected, this nanosystem could reprogram the TAM to achieve M1 macrophage activation and could also restore the potent tumor-killing activity of macrophages while switching their metabolic mode from mitochondrial oxidative phosphorylation to glycolysis. In addition, the repolarizing effect of SnSe NSs on macrophages was validated in a coculture model of bone marrow-derived macrophages, in three patient-derived malignant pleural effusion and in vivo mouse model. This study proposes a feasible therapeutic strategy for depleting lactate and thus ameliorating acidic TME employing Se-containing nanosheets, which could further amply the effects of TAM-based antitumor immunotherapy.

Acidic microenvironment triggered in situ assembly of activatable three-arm aptamer nanoclaw for contrast-enhanced imaging and tumor growth inhibition in vivo.

RATIONALE: Static assembled multivalent DNA nanotheranostics system have encountered some bottleneck problems in cancer imaging and therapy, such as poor penetration and high immunogenicity. Herein, we proposed an acidic tumor microenvironment triggered assembly of activatable multivalent nanodevice, called "three-arm aptamer nanoclaw" (TA-aptNC), assembled from three pH-responsive aptamer-decorated DNA monomers (pH-aptDMs) to facilitate their functions of imaging and therapy. METHODS: The activated TA-aptNC was constructed by acidic microenvironment triggered in situ assembly of three pH-aptDMs. Designer pH-aptDM was established based on the combination of a pH-responsive i-motif switch and an assembly module with a cell membrane anchoring aptamer ligand. Acidic microenvironment-triggered the assembly of the TA-aptNC was characterized by electrophoresis and atomic force microscopic (AFM). The binding affinity and stability of the TA-aptNC, comparing the monovalent pH-aptDM, were studied via the flow cytometry and nuclease resistance assays. Acidic microenvironment-activated contrast-enhanced tumor imaging and significantly antitumor efficiency were evaluated in vitro and in vivo. Results: At physiological pH environment, the pH-aptDMs with excellent tissue permeability exited as inactivated and monodispersed small monomer. When encountering acidic microenvironment at the tumor site, pH-responsive i-motif switch liberated from the pH-aptDMs, and the three unconstrained DNA modules (DM1, DM2 and DM3) subsequently assembled in situ into the TA-aptNC. Compared with monovalent pH-aptDMs, the spontaneously formed activatable TA-aptNC afforded 2-fold enhanced binding ability via the multivalent effect, which further facilitated the selective tumor cell uptake capability, thus enabling a contrast-enhanced tumor imaging and significantly antitumor efficiency in vivo without systemic toxicity. Conclusions: The proposed strategy offers valuable insight into excavating an endogenous stimuli-triggered assembly of multivalent nanodevice for accurate diagnosis and efficient tumor therapy.

miR-7/TGF-ß2 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-ß2 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-7-5p. TGF-ß2 is a direct target of miR-7-5p. The reduced expression of miR-7-5p subsequently increases the expression of TGF-ß2 which enhances the metastatic potential of the lung cancer. Indeed, overexpression of miR-7-5p reduces the acidic pH-enhanced lung cancer metastasis. Furthermore, the human lung tumor samples also show a reduced miR-7-5p expression but an elevated level of activated TGF-ß2; the expressions of both miR-7-5p and TGF-ß2 are correlated with patients' survival. We are the first to identify the role of the miR-7/TGF-ß2 axis in acidic pH-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 pH-sensitive subcellular components as novel therapeutic targets for cancer treatment.

Self-Enhanced Acoustic Impedance Difference Strategy for Detecting the Acidic Tumor Microenvironment.

B-mode ultrasound imaging is a significant anatomic technique in clinic, which can display the anatomic variation in tissues. However, it is difficult to evaluate the functional state of organs and display the physiological information in organisms such as the tumor acidic microenvironment (TME). Herein, inspired by the phenomenon of sonographic acoustic shadow during detecting calculus in clinic, a strategy of self-enhanced acoustic impedance difference is proposed to monitor the acidic TME. BiF3@PDA@PEG (BPP) nanoparticles can self-aggregate in a specific response to the acidic TME to form huge "stones" BiF3@PDA, resulting in an increase of local tumor density, and further causing a significant acoustic impedance difference. In in vitro experiments, the enhanced ultrasound signals change from 15.2 to 196.4 dB, which can discriminate different pH values from 7.0 to 5.0, and the sensitivity can reach to 0.2 value. In in vivo experiments, the enhanced ultrasound signal is 107.7 dB after BPP self-aggregated, displaying the weak acidic TME that has a close relationship with the size and species of the tumor. More importantly, the accuracy is away from the interference of pressure because huge "stones" BiF3@PDA change little. However, SonoVue microbubbles will diffuse and rupture under pressure, which results in false positive signals. To sum up, this strategy will be helpful to the further development of ultrasound molecular imaging.