Treatment Of Tumor Metastasis Research Articles

Neutrophil-targeted liposomal platform: a shift in novel approach for early detection and treatment of cancer metastasis

Tumor metastasis is responsible for 90% of cancer-associated deaths, and its early detection may decrease the likelihood of mortality. Studies have demonstrated that metastasis results from the interaction between “seeds” (tumor cells) and “soil” (pre-metastatic niche, PMN). As the first and most abundant immune cells to be recruited to PMN, neutrophils play a key role in the ultimate formation of metastatic foci through mechanisms such as supporting tumor cell growth, promoting angiogenesis, and shaping an immune-suppressive microenvironment. In this study, two distinct types of sialic acid (SA)-modified liposomes were prepared to target and regulate pro-metastatic neutrophils through the l-selectin receptor. One of these liposomes, named ICG@SAL, was used to encapsulate indocyanine green (ICG) and was specifically designed for the early detection of cancer metastasis. The other liposome, referred to as ABE/Cur@SAL, co-loaded abemaciclib (ABE) and curcumin (Cur), with the intention of suppressing the progression of metastatic tumor. Fluorescence imaging results from the mouse spontaneous metastasis model indicated that ICG@SAL demonstrated faster targeting and stronger accumulation in the metastatic organs than unmodified ICG liposomes (ICG@CL). This suggested that ICG@SAL could detect tumor metastasis at an early stage. The therapy with co-loaded liposomes in the mouse experimental lung metastasis model indicated that ABE/Cur@SAL could inhibit regulatory T (Treg) cell proliferation, enhance effector T cell activity and reduce tumorigenic factor release, implying that ABE/Cur@SAL could inhibit tumor metastasis. Overall, our work provided a sensitive and convenient approach to early diagnosis and treatment of tumor metastasis. ICG@SAL could be employed for the early detection of tumor metastasis, while ABE/Cur@SAL could be used to inhibit the development of tumor metastasis when early metastasis was identified.

Engineering an Organic Nanoplatform for Augmented Pyroeletroimmunotherapy.

Photothermal immunotherapy has shown great promise in the treatment of tumor metastasis. However, the thermal resistance of tumor cells substantially compromises the treatment effect of photothermal immunotherapy. Herein, a high-performance organic pyroelectric nanoplatform, tBu-TPAD-BF2 nanoparticles (NPs), is rationally engineered for the effective pyroelectroimmunotherapy of tumor metastasis. Biocompatible tBu-TPAD-BF2 NPs with excellent pyroelectric and photothermal conversion properties are constructed by assembling organic, low-bandgap pyroelectric molecules with amphiphilic polymers. After internalization by tumor cells, treatment with tBu-TPAD-BF2 NPs causes an apparent temperature elevation upon near-infrared (NIR) laser irradiation, inducing potent immunogenic cell death (ICD). Additionally, the temperature variations under alternating NIR laser irradiation facilitate reactive oxygen species production for pyroelectric therapy, thus promoting ICD activation and lowering thermal resistance. Importantly, in vivo assessments illustrate that tBu-TPAD-BF2 NPs in combination with NIR laser exposure notably inhibit primary and distant tumor proliferation and prominently retarded lung metastasis. RNA profiling reveals that treatment with tBu-TPAD-BF2 NPs markedly suppresses metastasis under NIR laser illumination by downregulating metastasis-related genes and upregulating immune response-associated pathways. Therefore, this study provides a strategy for designing high-performance pyroelectric nanoplatforms to effectively cure tumor metastasis, thereby overcoming the inherent shortcomings of photothermal immunotherapy.

Nanomaterial-Based Strategies for Preventing Tumor Metastasis by Interrupting the Metastatic Biological Processes.

Tumor metastasis is the primary cause of cancer-related deaths. The prevention of tumor metastasis has garnered notable interest and interrupting metastatic biological processes is considered a potential strategy for preventing tumor metastasis. The tumor microenvironment (TME), circulating tumor cells (CTCs), and premetastatic niche (PMN) play crucial roles in metastatic biological processes. These processes can be interrupted using nanomaterials due to their excellent physicochemical properties. However, most studies have focused on only one aspect of tumor metastasis. Here, the hypothesis that nanomaterials can be used to target metastatic biological processes and explore strategies to prevent tumor metastasis is highlighted. First, the metastatic biological processes and strategies involving nanomaterials acting on the TME, CTCs, and PMN to prevent tumor metastasis are briefly summarized. Further, the current challenges and prospects of nanomaterials in preventing tumor metastasis by interrupting metastatic biological processes are discussed. Nanomaterial-and multifunctional nanomaterial-based strategies for preventing tumor metastasis are advantageous for the long-term fight against tumor metastasis and their continued exploration will facilitate rapid progress in the prevention, diagnosis, and treatment of tumor metastasis. Novel perspectives are outlined for developing more effective strategies to prevent tumor metastasis, thereby improving the outcomes of patients with cancer.

Key processes in tumor metastasis and therapeutic strategies with nanocarriers: a review.

Cancer metastasis is the leading cause of cancer-related death. Metastasis occurs at all stages of tumor development, with unexplored changes occurring at the primary site and distant colonization sites. The growing understanding of the metastatic process of tumor cells has contributed to the emergence of better treatment options and strategies. This review summarizes a range of features related to tumor cell metastasis and nanobased drug delivery systems for inhibiting tumor metastasis. The mechanisms of tumor metastasis in the ideal order of metastatic progression were summarized. We focus on the prominent role of nanocarriers in the treatment of tumor metastasis, summarizing the latest applications of nanocarriers in combination with drugs to target important components and processes of tumor metastasis and providing ideas for more effective nanodrug delivery systems.

Clinically approved carbon nanoparticles for enhanced photothermal-immunotherapy toward cancer metastasis

The development of new biomedical applications of approved drugs has several advantages in drug translation. In this study, carbon nanoparticle suspension injection (CNSI), clinically approved for lymph node tracer in China, is explored as a photothermal conversion agents for the treatment of metastatic cancer. Metastasis commonly through lymphatic circulation accounts for the principal cause of death in cancer patients. Up to now, immunotherapy has been already used clinically for metastatic cancer. However, the suppressive tumor immune microenvironment limits the effectiveness of immunotherapy. Herein, we use the photothermal effect of CNSI under near-infrared (NIR) irradiation to eliminate primary tumor and induce the immunogenic cell death (ICD). Further, CNSI under irradiation combined with aPD-1 spur immune response and inhibit the growth of distal tumors. Except for the primary tumor, phototherapy was used to treat metastatic lymph nodes synchronously, which can not only eradicate cancer cells, but also directly activate the immune response inside the lymph nodes. Combining with aPD-1 further enhance the anti-tumor effect to block lymphatic metastases and inhibit lung metastases. This study shows that the carbon nanoparticles have potential clinical application prospects for the treatment of tumor metastasis.

Cancer cells reprogram to metastatic state through the acquisition of platelet mitochondria

Metastasis is the major cause of cancer deaths, and cancer cells evolve to adapt to various tumor microenvironments, which hinders the treatment of tumor metastasis. Platelets play critical roles in tumor development, especially during metastasis. Here, we elucidate the role of platelet mitochondria in tumor metastasis. Cancer cells are reprogrammed to a metastatic state through the acquisition of platelet mitochondria via the PINK1/Parkin-Mfn2 pathway. Furthermore, platelet mitochondria regulate the GSH/GSSG ratio and reactive oxygen species (ROS) in cancer cells to promote lung metastasis of osteosarcoma. Impairing platelet mitochondrial function has proven to be an efficient approach to impair metastasis, providing a direction for osteosarcoma therapy. Our findings demonstrate mitochondrial transfer between platelets and cancer cells and suggest a role for platelet mitochondria in tumor metastasis.

RWTC-MBTA: autologous vaccine prevents metastases via antitumor immune responses

BackgroundAutologous tumor cell-based vaccines (ATVs) aim to prevent and treat tumor metastasis by activating patient-specific tumor antigens to induce immune memory. However, their clinical efficacy is limited. Mannan-BAM (MB), a pathogen-associated molecular pattern (PAMP), can coordinate an innate immune response that recognizes and eliminates mannan-BAM-labeled tumor cells. TLR agonists and anti-CD40 antibodies (TA) can enhance the immune response by activating antigen-presenting cells (APCs) to present tumor antigens to the adaptive immune system. In this study, we investigated the efficacy and mechanism of action of rWTC-MBTA, an autologous whole tumor cell vaccine consisting of irradiated tumor cells (rWTC) pulsed with mannan-BAM, TLR agonists, and anti-CD40 antibody (MBTA), in preventing tumor metastasis in multiple animal models.MethodsThe efficacy of the rWTC-MBTA vaccine was evaluated in mice using breast (4T1) and melanoma (B16-F10) tumor models via subcutaneous and intravenous injection of tumor cells to induce metastasis. The vaccine’s effect was also assessed in a postoperative breast tumor model (4T1) and tested in autologous and allogeneic syngeneic breast tumor models (4T1 and EMT6). Mechanistic investigations included immunohistochemistry, immunophenotyping analysis, ELISA, tumor-specific cytotoxicity testing, and T-cell depletion experiments. Biochemistry testing and histopathology of major tissues in vaccinated mice were also evaluated for potential systemic toxicity of the vaccine.ResultsThe rWTC-MBTA vaccine effectively prevented metastasis and inhibited tumor growth in breast tumor and melanoma metastatic animal models. It also prevented tumor metastasis and prolonged survival in the postoperative breast tumor animal model. Cross-vaccination experiments revealed that the rWTC-MBTA vaccine prevented autologous tumor growth, but not allogeneic tumor growth. Mechanistic data demonstrated that the vaccine increased the percentage of antigen-presenting cells, induced effector and central memory cells, and enhanced CD4+ and CD8+ T-cell responses. T-cells obtained from mice that were vaccinated displayed tumor-specific cytotoxicity, as shown by enhanced tumor cell killing in co-culture experiments, accompanied by increased levels of Granzyme B, TNF-α, IFN-γ, and CD107a in T-cells. T-cell depletion experiments showed that the vaccine’s antitumor efficacy depended on T-cells, especially CD4+ T-cells. Biochemistry testing and histopathology of major tissues in vaccinated mice revealed negligible systemic toxicity of the vaccine.ConclusionThe rWTC-MBTA vaccine demonstrated efficacy in multiple animal models through T-cell mediated cytotoxicity and has potential as a therapeutic option for preventing and treating tumor metastasis with minimal systemic toxicity.

Radionuclide-Labeled Microspheres for Radio-Immunotherapy of Hepatocellular Carcinoma.

Brachytherapy, including radioactive seed implantation (RSI) and transarterial radiation therapy embolization (TARE), is an important treatment modality for advanced hepatocellular carcinoma (HCC), but the inability of RSI and TARE to treat tumor metastasis and recurrence limits their benefits for patients in the clinic. Herein, indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors-loaded alginate microspheres (IMs) are developed as radionuclide carriers with immunomodulatory functions to achieve effective radio-immunotherapy. The size and swelling properties of IMs can be facilely tailored by adjusting the calcium source during emulsification. Small/large IMs(SIMs/LIMs) are biocompatible and available for RSI and TARE, respectively, after 177 Lu labeling. Among them, 177 Lu-SIMs completely eliminated subcutaneous HCC in mice after intratumoral RSI. Moreover, in combination with anti-PD-L1, 177 Lu-SIMs not only eradicate primary tumors by RSI but also effectively inhibit the growth of distant tumors, wherein the potent abscopal effect can be ascribed to the immune stimulation of RSI and the modulation of the tumor immune microenvironment (TIME) by IDO1 inhibitors. In parallel, LIMs demonstrate excellent embolization efficiency, resulting in visible necrotic lesions in the central auricular artery of rabbits, which are promising for TARE in future studies. Collectively, a versatile therapeutic agent is provided to synchronously modulate the TIME during brachytherapy for efficient radio-immunotherapy of advanced HCC.

Multivalent dipeptidyl peptidase IV fragment-nanogold complex inhibits cancer metastasis by blocking pericellular fibronectin

Inhibition of cancer metastasis is a fundamental challenge in cancer treatment. We have previously shown that metastasis of cancer cells in the lung is critically promoted by the interaction between the superficial dipeptidyl peptidase IV (DPP IV) expressed on lung endothelial cells and the pericellular polymeric fibronectin (polyFN) of circulating cancer cells. In the present study, we aimed to search for DPP IV fragments with high avidity to polyFN and develop FN-targeted gold nanoparticles (AuNPs) conjugated with DPP IV fragments for treating cancer metastasis. We first identified a DPP IV fragment encompassing amino acids 29-130 of DPP IV, designated DP4A, which contained FN-binding sites and could specifically bind to FN immobilized on gelatin agarose beads. Furthermore, we conjugated maltose binding protein (MBP)-fused DP4A proteins to AuNPs for fabricating a DP4A-AuNP complex and evaluated its FN-targeted activity in vitro and anti-metastatic efficacy in vivo. Our results show that DP4A-AuNP exhibited higher binding avidity to polyFN than DP4A by 9 folds. Furthermore, DP4A-AuNP was more potent than DP4A in inhibiting DPP IV binding to polyFN. In terms of polyFN-targeted effect, DP4A-AuNP interacted with FN-overexpressing cancer cells and was endocytosed into cells 10 to 100 times more efficiently than untargeted MBP-AuNP or PEG-AuNP with no noticeable cytotoxicity. Furthermore, DP4A-AuNP was superior to DP4A in competitive inhibition of cancer cell adhesion to DPP IV. Confocal microscopy analysis revealed that binding of DP4A-AuNP to pericellular FN induced FN clustering without altering its surface expression on cancer cells. Notably, intravenous treatment with DP4A-AuNP significantly reduced metastatic lung tumor nodules and prolonged the survival in the experimental metastatic 4T1 tumor model. Collectively, our findings suggest that the DP4A-AuNP complex with potent FN-targeted effects may have therapeutic potential for prevention and treatment of tumor metastasis to the lung.

Enhance Mitochondrial Damage by Nuclear Export Inhibition to Suppress Tumor Growth and Metastasis with Increased Antitumor Properties of Macrophages.

Mitochondria-targeting damage has become a popular therapeutic option for tumor metastasis; however, its efficacy is limited by the adaptive rescue capacity of nuclei. There is an urgent need for a dual mitochondrial and nuclear targeting strategy that can also increase the antitumor capacity of macrophages. In this study, XPO1 inhibitor KPT-330 nanoparticles were combined with mitochondria-targeting lonidamine (TPP-LND) nanoparticles. The combination of nanoparticles with a 1:4 ratio of KPT and TL demonstrated the best synergistic effect in restraining the proliferation and metastasis of 4T1 breast cancer cells. Investigating the mechanisms both in vitro and in vivo, it was found that KPT nanoparticles not only directly impede tumor growth and metastasis by controlling the expression of associated proteins but also indirectly facilitate mitochondrial damage. The two nanoparticles synergistically decreased the expression of cytoprotective factors, such as Mcl-1 and Survivin, causing mitochondrial dysfunction and thus inducing apoptosis. Additionally, it downregulated metastasis-related proteins like HIF-1α, vascular endothelial growth factor (VEGF), and matrix metalloproteinase 2 (MMP-2) and reduced endothelial-to-mesenchymal transition. Significantly, their combination increased the ratio of M1 tumor-associated macrophages (TAMs)/M2 TAMs both in vitro and in vivo and increased the phagocytosis of tumor cells by macrophages, thus suppressing tumor growth and metastasis. In summary, this research revealed that nuclear export inhibition can synergistically enhance the prevention of mitochondrial damage to tumor cells, heightening the antitumor properties of TAMs, thereby providing a viable and safe therapeutic approach for the treatment of tumor metastasis.

Abstract 6800: Unique autologous cancer vaccine comprised of irradiated whole tumor cells and MBTA (rWTC-MBTA) triggers antitumor immune response to prevent metastasis

Abstract Despite the advances made in cancer treatment over the past decades, one statistic has remained unchanged: metastatic cancer accounts for 90 percent of annual cancer deaths in the United States. Our group previously demonstrated that an autologous whole tumor cell vaccine (rWTC-MBTA: irradiated autologous whole tumor cells pulsed with Mannan-BAM, TLR ligands, and anti-CD40 antibody) had a potent anti-tumor immune response and prolonged survival in a mouse colon carcinoma model. To investigate whether rWTC-MBTA would work in “cold” tumor models, we evaluated the vaccine’s effect on preventing and treating tumor metastasis in 4T1 breast tumors. Our data showed that vaccinated mice could significantly prevent lung metastasis in both intravenous injection and mammary pad subcutaneous implantation animal models. Further, we used another metastasis model that more closely mimics clinical practice by resecting the primary tumor after metastasis development. The data showed that vaccinated mice could prevent tumor recurrence, increase T-cell infiltration in the metastatic tumor, and prolong the survival curve. The mechanistic investigation by immunophenotyping revealed that rWTC-MBTA vaccination induced both effector memory (CD44+CD62L−) and center memory (CD44+CD62L+) T cells as well as increased overall CD4+ and CD8+ T-cell count while depletion experiments demonstrated that CD8+ T cells were required for vaccine efficacy. Isolated splenocytes co-cultured with 4T1 cells showed rWTC-MBTA significantly increased T-cell mediated cytotoxicity through TNF-a and IFN-γ in CD107a+CD4+ T cells and Granzyme B and IFN-γ in CD107a+CD8+ T cells. In all experiments, vaccination exerted negligible systemic toxicity. Collectively, our study demonstrates that the rWTC-MBTA vaccine is a safe and promising therapeutic option to prevent and treat tumor metastasis by triggering an antitumor immune response. Citation Format: Juan Ye, Herui Wang, Mitchell Sun, Ondrej Uher, Mark R. Gilbert, Karel Pacak, Zhengping Zhuang, Rogelio Medina, Samik Chakraborty, Jan Zenka. Unique autologous cancer vaccine comprised of irradiated whole tumor cells and MBTA (rWTC-MBTA) triggers antitumor immune response to prevent metastasis. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6800.

Removal of ferroptosis barrier mediated by nanoengineering platform for the treatment of tumor lymphatic metastasis

Malignant cells usually metastasize locally through the lymphatic system before systematically through the blood. Importantly, malignant cell membrane after lymphatic metastasis has a higher proportion of oleic acid (OA), a monounsaturated fatty acid, which has been proven to protect malignant cells from ferroptosis after entering the blood with high oxidative stress and promote the occurrence of metastatic tumors. However, no effective strategy has been developed to remove OA on the malignant cell membrane after lymphatic metastases so far. Malignant cells after lymphatic metastasis often upregulate their ferroptosis defense systems, including GPX4-GSH system and FSP1-CoQH2 system, to achieve ferroptosis evasion. Recently, chemodynamic therapy (CDT) has been widely used in preclinical research of malignant tumor treatment with satisfactory results. However, whether CDT can be used to remove the ferroptosis barrier including OA and ferroptosis defense systems so as to induce ferroptosis of tumor cells has not been confirmed. Herein, for the first time, we show that CDT nanoengineering platform (NEP) can remove ferroptosis-inhibitory OA and inactivate ferroptosis defense system to clean the path of ferroptosis therapy for tumor lymphatic metastasis. This strategy implies a general principle for the treatment of tumor metastasis by targeted ferroptosis, which may boost the research and clinical translation of ferroptosis as a promising therapeutic pattern for tumor metastasis treatment.

Inhibitory Effect of Astragalus Polysaccharide on Premetastatic Niche of Lung Cancer through the S1PR1-STAT3 Signaling Pathway.

As a common malignant tumor, the morbidity and mortality of lung cancer have been rising in recent years. The concept of "premetastatic niche" may lead to a revolutionary change in antitumor metastasis therapeutic strategies. Traditional Chinese medicine with multitargets and lower poisonous agents may be a potentially effective means to intervene in the "premetastatic niche (PMN)" to prevent and treat tumor metastasis. Astragalus polysaccharide (APS) is a substance with strong immune activity in Astragalus membranaceus that has excellent biological activities such as immunomodulation, anti-inflammatory, and antitumor. In this study, we constructed a tumor lung metastasis animal model to explore the intervention mechanism of APS on the premetastatic niche. We found that APS inhibited the formation of the lung premetastatic niche and inhibited the recruitment of myeloid-derived suppressor cells (MDSCs) in the lung. Mechanistically, we showed that the proteins and gene expression of S1PR1, STAT3, and p-STAT3 in the S1PR1/STAT3 signaling pathway were suppressed by APS. In line with the above findings, our results confirmed that APS may inhibit the accumulation of MDSCs in the premetastatic niche through the intervention of the S1PR1-STAT3 signaling pathway to achieve the antitumor effect.

B cells in tumor metastasis: friend or foe?

Metastasis is an important cause of cancer-related death. Immunotherapy may be an effective way to prevent and treat tumor metastasis in the future. Currently, many studies have focused on T cells, whereas fewer have focused on B cells and their subsets. B cells play an important role in tumor metastasis. They not only secrete antibodies and various cytokines but also function in antigen presentation to directly or indirectly participate in tumor immunity. Furthermore, B cells are involved in both inhibiting and promoting tumor metastasis, which demonstrates the complexity of B cells in tumor immunity. Moreover, different subgroups of B cells have distinct functions. The functions of B cells are also affected by the tumor microenvironment, and the metabolic homeostasis of B cells is also closely related to their function. In this review, we summarize the role of B cells in tumor metastasis, analyze the mechanisms of B cells, and discuss the current status and prospects of B cells in immunotherapy.

Non-Coding RNAs of Extracellular Vesicles: Key Players in Organ-Specific Metastasis and Clinical Implications.

Extracellular vesicles (EVs) are heterogeneous membrane-encapsulated vesicles released by most cells. They act as multifunctional regulators of intercellular communication by delivering bioactive molecules, including non-coding RNAs (ncRNAs). Metastasis is a major cause of cancer-related death. Most cancer cells disseminate and colonize a specific target organ via EVs, a process known as "organ-specific metastasis". Mounting evidence has shown that EVs are enriched with ncRNAs, and various EV-ncRNAs derived from tumor cells influence organ-specific metastasis via different mechanisms. Due to the tissue-specific expression of EV-ncRNAs, they could be used as potential biomarkers and therapeutic targets for the treatment of tumor metastasis in various types of cancer. In this review, we have discussed the underlying mechanisms of EV-delivered ncRNAs in the most common organ-specific metastases of liver, bone, lung, brain, and lymph nodes. Moreover, we summarize the potential clinical applications of EV-ncRNAs in organ-specific metastasis to fill the gap between benches and bedsides.

Partial advances in the diagnosis and treatment of gastrointestinal cancer.

Partial advances in the diagnosis and treatment of gastrointestinal cancer.

Chemo-Phototherapy with Carfilzomib-Encapsulated TiN Nanoshells Suppressing Tumor Growth and Lymphatic Metastasis.

The design of nanomedicine for cancer therapy, especially the treatment of tumor metastasis has received great attention. Proteasome inhibition is accepted as a new strategy for cancer therapy. Despite being a big breakthrough in multiple myeloma therapy, carfilzomib (CFZ), a second-in-class proteasome inhibitor is still unsatisfactory for solid tumor and metastasis therapy. In this study, hollow titanium nitride (TiN) nanoshells are synthesized as a drug carrier of CFZ. The TiN nanoshells have a high loading capacity of CFZ, and their intrinsic inhibitory effect on autophagy synergistically enhances the activity of CFZ. Due to an excellent photothermal conversion efficiency in the second near-infrared (NIR-II) region, TiN nanoshell-based photothermal therapy further induces a synergistic anticancer effect. In vivo study demonstrates that TiN nanoshells readily drain into the lymph nodes, which are responsible for tumor lymphatic metastasis. The CFZ-loaded TiN nanoshell-based chemo-photothermal therapy combined with surgery offers a remarkable therapeutic outcome in greatly inhibiting further metastatic spread of cancer cells. These findings suggest that TiN nanoshells act as an efficient carrier of CFZ for realizing enhanced outcomes for proteasome inhibitor-based cancer therapy, and this work also presents a "combined chemo-phototherapy assisted surgery" strategy, promising for future cancer treatment.

Application of Microfluidics in Detection of Circulating Tumor Cells.

Tumor metastasis is one of the main causes of cancer incidence and death worldwide. In the process of tumor metastasis, the isolation and analysis of circulating tumor cells (CTCs) plays a crucial role in the early diagnosis and prognosis of cancer patients. Due to the rarity and inherent heterogeneity of CTCs, there is an urgent need for reliable CTCs separation and detection methods in order to obtain valuable information on tumor metastasis and progression from CTCs. Microfluidic technology is increasingly used in various studies of CTCs separation, identification and characterization because of its unique advantages, such as low cost, simple operation, less reagent consumption, miniaturization of the system, rapid detection and accurate control. This paper reviews the research progress of microfluidic technology in CTCs separation and detection in recent years, as well as the potential clinical application of CTCs, looks forward to the application prospect of microfluidic technology in the treatment of tumor metastasis, and briefly discusses the development prospect of microfluidic biosensor.

Therapeutic effects of mesenchymal stem cells loaded with oncolytic adenovirus carrying decorin on a breast cancer lung metastatic mouse model

Oncolytic adenoviruses (OAds) are alternative immune therapeutic strategies for tumors. However, liver uptake and antibody neutralization are two major barriers for systemic delivery during the treatment of tumor metastasis. Mesenchymal stem cells (MSCs) have emerged as potential vehicles to improve delivery. In this study, we loaded umbilical-cord-derived MSCs (UC-MSCs) with OAds expressing decorin (rAd.DCN) or without foreign genes (rAd.Null) to treat breast cancer lung metastasis. In vivo, rAd.Null, MSCs.Null, and rAd.DCN exhibited antitumor effects compared with other groups in a mouse model. Unexpectedly, MSCs.Null showed much greater antitumor responses than MSCs.DCN, including improved survival and reduced tumor burden. Compared with rAd.Null, both MSCs.Null and MSCs.DCN could improve the viral spread and distribution in metastatic tumor lesions in the lung. MSCs.DCN produced much more decorin in lungs than rAd.DCN; however, rAd.DCN reduced the downstream target genes of decorin much more strongly than MSCs.DCN, which was consistent with in vitro findings. In addition, rAd.DCN, MSCs.Null, and MSCs.DCN could reduce The cytokine levels in the lung. In conclusion, MSCs improved oncolytic adenoviral delivery and spread in tumor tissues and enhanced therapeutic effects. However, MSCs.DCN reduced OAd-evoked antitumor responses, possibly via a contact-dependent mechanism.

Pirfenidone-loaded exosomes derived from pancreatic ductal adenocarcinoma cells alleviate fibrosis of premetastatic niches to inhibit liver metastasis.

Given the metastasis-promoting effect of pancreatic ductal adenocarcinoma (PDAC)-derived exosomes through activation of fibrotic premetastatic niches, targeting and intervening in premetastatic organs to inhibit distant metastasis have challenged researchers and clinicians. Herein, a self-biomimetic drug delivery system based on exosomes derived from PDAC (PF@PCCEs) was constructed to precisely deliver an antifibrotic drug (pirfenidone, PF) to fibrotic premetastatic organs. First, PDAC-derived exosomes were confirmed to remarkably promote liver fibrosis. Then the prepared PF@PCCEs were actively internalized by HSCs (hepatic stellate cells) and subsequently alleviated the activation of HSCs. Delivery of PF to the premetastatic liver affected the niche suitable for the colonization of circulating tumour cells, further suppressing liver metastasis of PDAC. Thus, the strategy for intervening in the formation of fibrotic premetastatic niches to inhibit liver metastasis of PDAC using PF@PCCEs might offer inspiration for the treatment of tumour metastasis.