Cancer is one of the leading causes of death worldwide, and the factors responsible for its progression need to be elucidated. Exosomes are structures with an average size of 100 nm that can transport proteins, lipids, and nucleic acids. This review focuses on the role of exosomes in cancer progression and therapy. We discuss how exosomes are able to modulate components of the tumor microenvironment and influence proliferation and migration rates of cancer cells. We also highlight that, depending on their cargo, exosomes can suppress or promote tumor cell progression and can enhance or reduce cancer cell response to radio- and chemo-therapies. In addition, we describe how exosomes can trigger chronic inflammation and lead to immune evasion and tumor progression by focusing on their ability to transfer non-coding RNAs between cells and modulate other molecular signaling pathways such as PTEN and PI3K/Akt in cancer. Subsequently, we discuss the use of exosomes as carriers of anti-tumor agents and genetic tools to control cancer progression. We then discuss the role of tumor-derived exosomes in carcinogenesis. Finally, we devote a section to the study of exosomes as diagnostic and prognostic tools in clinical courses that is important for the treatment of cancer patients. This review provides a comprehensive understanding of the role of exosomes in cancer therapy, focusing on their therapeutic value in cancer progression and remodeling of the tumor microenvironment. 

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Emerging role of exosomes in cancer progression and tumor microenvironment remodeling

Background Neoadjuvant chemotherapy is increasingly the treatment for patients with inoperable breast cancer. Considering the side-effects of chemotherapy, there is a need for early evaluating response to neoadjuvant chemotherapy. Purpose To determinate the diagnostic performance of 18F-fluorodeoxyglucose position emission tomography/computed tomography (FDG PET/CT) and FDG PET for evaluating response to neoadjuvant chemotherapy in patients with breast cancer. Material and Methods “PubMed” (MEDLINE included) database, EMBASE, and Cochrane Database of Systematic Reviews were searched for relevant articles. We assessed the methodological quality of included study with Quality Assessment of Diagnosis Accuracy Studies (QUADAS) score tool, and used “Meta-DiSc” statistic software to obtain pooled estimates of sensitivity, specificity, diagnostic odds ratio (DOR), and summary receiver-operating characteristic (SROC) curve. Results Seventeen studies (a total of 781 subjects) met the inclusion criteria. The pooled sensitivity was 0.840 (95% confidence interval [CI] 0.796–0.878). The pooled specificity was 0.713 (95% CI 0.667–0.756). For FDG PET/CT (10 studies included), the pooled sensitivity was 0.847 (95% CI 0.793–0.892), the pooled specificity was 0.661 (95% CI 0.598–0.720). The pooled likelihood ratio (LR+), negative likelihood ratio (LR–), and diagnostic odds ratio (DOR) were 2.835 (95% CI 1.640–4.900), 0.221 (95% CI 0.160–0.305), and 17.628 (95% CI 7.431–41.818). The area under the SROC curve (AUC) was 0.8934. For FDG PET (7 studies included), the pooled sensitivity and specificity were 0.826 (95% CI 0.741–0.892) and 0.789 (95% CI 0.719–0.849). The pooled LR + , LR–, and DOR were 3.601 (95% CI 2.601–4.986), 0.242 (95% CI 0.157–0.374), and 13.641 (95% CI 7.433–25.030). The AUC was 0.8764. Conclusion Our results indicate that FDG PET/CT and PET have reasonable sensitivity in evaluating response to neoadjuvant chemotherapy in breast cancer; however, the specificity is relative low. The combination of other imaging methods with FDG PET/CT or PET is recommended.

18F-FDG PET/CT and PET for evaluation of pathological response to neoadjuvant chemotherapy in breast cancer: A meta-analysis

The application of immune checkpoint blockade in breast cancer and the emerging role of nanoparticle.

Feasibility and reliability of sentinel lymph node biopsy after neoadjuvant chemotherapy in breast cancer patients with positive axillary nodes at initial diagnosis: An up-to-date meta-analysis of 3,578 patients.

Background: Disruption of Tight Junctions (TJ9s) in endothelial cells can cause a leaky vascular bed and may therefore lead to vascular spread of cancer cells. Hepatitis A virus (HAV) cellular receptor HAVcR-1, also known as KIM-1/TIM-1, is the cellular receptor for the hepatotropic picornavirus that causes acute hepatitis-A in humans. Although HAVcR-1 is expressed in every human organ, the natural function of HAVcR-1 remains unknown. In the current study, we investigated the location, association and possible functionality of HAVcR-1 in human endothelial cells. Methods: HAVcR-1 protein in human endothelial cells was visualised using immunohistochemistry and mRNA transcript by RT-PCR. A hammerhead ribozyme transgene that specifically targeted human HAVcR-1 was constructed and used to knockdown endogenously expressed HAVcR-1 (HECV HKD ); moreover, forced expression was obtained by insertion of a transgene into wild type endothelial cells (HECV HEX ).TJ function was assessed using trans-endothelial resistance (TER) and paracellular permeability assays under the influence of HGF (40ng/ml) a cytokine we have previously shown to modulate TJs in human endothelial cells. Results: Human endothelial cells expressed HAVcR-1 at low levels. The location of both endogenous and forcibly expressed HAVcR-1 was at the cell-cell junction, at the region of the TJ. In this study, one of the first to examine the location and binding partners of HAVcR-1, expression of this receptor was targeted to the vicinity of intercellular junctions, via ZO-1, which further was demonstrated to be at the site of the TJ by its co-localisation with ZO-2. This was true of both endogenously and forcibly expressed protein. Moreover, HAVcR-1 was co-precipitated with the regulatory factor Rho C. Although there was no change in function of HECV HEX cells, the TJ function of the HECV HKD cells exhibited significantly reduced response to HGF over 2h (p Conclusion: These results demonstrate for the first time that HAVcR-1 may have a previously undiscovered role in the regulation of TJ integrity in human endothelial cells. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 2158.

The Hepatitis A Virus Cellular Receptor, HAVcR-1, Reduces the Integrity of Human Endothelial Tight Junctions.

Breast cancer (BC) is a malignancy with high incidence among women in the world. This study aims to screen key genes and potential prognostic biomarkers for BC using bioinformatics analysis. Total 58 normal tissues and 203 cancer tissues were collected from three Gene Expression Omnibus (GEO) gene expression profiles, and then the differential expressed genes (DEGs) were identified. Subsequently, the Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genome (KEGG) pathway were analyzed to investigate the biological function of DEGs. Additionally, hub genes were screened by constructing a protein-protein interaction (PPI) network. Then, we explored the prognostic value and molecular mechanism of these hub genes using Kaplan-Meier (KM) curve and Gene Set Enrichment Analysis (GSEA). As a result, 42 up-regulated and 82 down-regulated DEGs were screened out from GEO datasets. The DEGs were mainly related to cell cycles and cell proliferation by GO and KEGG pathway analysis. Furthermore, 12 hub genes (FN1, AURKA, CCNB1, BUB1B, PRC1, TPX2, NUSAP1, TOP2A, KIF20A, KIF2C, RRM2, ASPM) with a high degree were identified initially, among which, 11 hub genes were significantly correlated with the prognosis of BC patients based on the Kaplan-Meier-plotter. GSEA reviewed that these hub genes correlated with KEGG_CELL_CYCLE and HALLMARK_P53_PATHWAY. In conclusion, this study identified 11 key genes as BC potential prognosis biomarkers on the basis of integrated bioinformatics analysis. This finding will improve our knowledge of the BC progress and mechanisms.

https://www.tandfonline.com/doi/pdf/10.1080/21655979.2021.1960775

Identification of candidate biomarkers correlated with poor prognosis of breast cancer based on bioinformatics analysis.

Objective: Although T-cell immunoglobulin and mucin-domain containing molecule-3 (Tim-3) has been recognized as a promising target for cancer immunotherapy, its exact role in breast cancer has not been fully elucidated. Methods: Tim-3 gene expression in breast cancer and its prognostic significance were analyzed. Associated mechanisms were then explored in vitro by establishing Tim-3-overexpressing breast cancer cells. Results: In a pooled analysis of The Cancer Genome Atlas (TCGA) database, Tim-3 gene expression levels were significantly higher (P<0.001) in breast cancer tissue, compared with normal tissues. Tim-3 was a prognosis indicator in breast cancer patients [relapse-free survival (RFS), P=0.004; overall survival (OS), P=0.099]. Tim-3 overexpression in Tim-3low breast cancer cells promoted aggressiveness of breast cancer cells, as evidenced by enhanced proliferation, migration, invasion, tight junction deterioration and tumor-associated tubal formation. Tim-3 also enhanced cellular resistance to paclitaxel. Furthermore, Tim-3 exerted its function by activating the NF-κB/STAT3 signalling pathway and by regulating gene expression [cyclin D1 (CCND1), C-Myc, matrix metalloproteinase-1(MMP1), TWIST, vascular endothelial growth factor (VEGF) upregulation, concomitant with E-cadherin downregulation). Lastly, Tim-3 downregulated tight junction-associated molecules zona occludens (ZO)-2, ZO-1 and occludin, which may further facilitate tumor progression. Conclusions: Tim-3 plays an oncogenic role in breast cancer and may represent a potential target for antitumor therapy.

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Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells.

Background: Chemoresistance remains one of the obstacles to overcome in the treatment of breast cancer. S100 calcium-binding protein P (S100P) has been observed to be overexpressed in several cancers and has been associated with drug resistance, metastasis, and prognosis. However, the role of S100P in chemoresistance in breast cancer has not been thoroughly determined. Methods: Immunohistochemistry was used to evaluate the expression level of S100P protein in 22 pairs (pre-chemo and post-chemo) of breast cancer tissue from patients who underwent neoadjuvant chemotherapy. The influence of S100P on the biological behavior and chemosensitivity of breast cancer cells was then investigated. Results: The protein level of S100P in breast cancer tissue was significantly higher than in benign fibroadenoma (p<0.001). The S100P expression level was shown to be decreased by 46.55% after neoadjuvant chemotherapy (p=0.015). Subgroup analysis revealed that S100P reduction (57.58%) was mainly observed in the HER2+ tumors (p=0.027). Our in-vitro experiments showed that the knockdown of S100P suppressed the proliferation, adhesion, migration and invasion abilities of T47D and SK-BR-3 breast cancer cells. We further demonstrated that this knockdown increased the chemoresistance to paclitaxel and cisplatin in SK-BR-3 cells. We found that S100P exerted its function by activating NF-κB, CCND1 and Vimentin, but downregulating E-cadherin. Conclusions: S100P promotes the aggressive properties of breast cancer cells and may be considered as a promising therapeutic target. Moreover, S100P can be used to predict the therapeutic effect of chemotherapy in HER2+ breast cancer patients.

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Calcium-Binding Protein S100P Promotes Tumor Progression but Enhances Chemosensitivity in Breast Cancer

Purpose Seroma formation is a common complication in breast cancer patients undergoing mastectomy, and it negatively affects patient recovery after surgery. The present study aimed to evaluate a simple method using fascia suture technique to fix the flap and reduce the incidence of seroma. Methods A single-center, prospective, randomized controlled trial was carried out among 160 patients who had undergone mastectomy from May 2018 to September 2019. All patients were randomly divided into the fascia suture group (n = 80) or control group (n = 80) and were followed up for at least 3 months for the assessment of immediate and late complications after surgery. Results No significant differences were observed between the 2 groups with regard to the basic characteristics. Duration of surgery in the fascia suture group was longer by about 6 minutes compared with that in the control group (114.93 ± 13.67 minutes vs. 108.81 ± 15.20 minutes, p = 0.008). The fascia suture group had a shorter duration of drain placement (10.99 ± 3.26 days vs. 13.85 ± 5.37 days, p 0.050). Conclusion The fascia suture technique is a simple and effective method for reducing seroma formation and should be used to prevent seroma formation after mastectomy. Trial registration Chinese Clinical Trials Registry Identifier: ChiCTR1800015913.

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Fascia Suture Technique Is a Simple Approach to Reduce Postmastectomy Seroma Formation.

PURPOSE To observe the efficacy of neoadjuvant chemotherapy (NAC) in patients with breast cancer (BC) and to investigate the effect of Annexin A3 (ANXA3) expression. METHODS 158 patients with BC treated in Yantai Yuhuangding Hospital from September 2015 to December 2017 were retrospectively analyzed. Among them, 83 cases were treated with epirubicin + cyclophosphamide + 5-fluorouracil (CEF group), 75 cases with epirubicin + cyclophosphamide + docetaxel (TEC group), with 3 cycles of chemotherapy. The efficacy and adverse reactions of the two NAC regimens were compared and analyzed. Tissue specimens were collected before and 10 days after the administration of chemotherapy in order to detect the expression of ANXA3 by qRT-PCR in each group. RESULTS There were significant differences in the rates of complete remission (CR), partial remission (PR), stable disease (SD), and progressive disease (PD) between the two groups (z=10.716, p=0.013). The clinical effectiveness rate in the TEC group was significantly higher than that in the CEF group (p 0.05); however, the pathological effective rate in the TEC group was significantly higher than that in the CEF group (p 0.05). While there was no difference in the relative expression of ANXA3 between the two groups before chemotherapy, the relative expression of ANXA3 in the TEC group was lower than that in the CEF group after NAC (p<0.05). The relative expression in both groups after chemotherapy was lower than that before NAC (P<0.05). CONCLUSION Compared with CEF regimen, NAC with TEC regimen can improve the clinical and pathological effectiveness rate, inhibit the expression of ANXA3, and improve the prognosis of patients, thus having a certain application prospect in NAC.

Jianqiao Cao

Papers

Identification of candidate biomarkers correlated with poor prognosis of breast cancer based on bioinformatics analysis.

Tim-3 promotes cell aggressiveness and paclitaxel resistance through NF-κB/STAT3 signalling pathway in breast cancer cells.

Calcium-Binding Protein S100P Promotes Tumor Progression but Enhances Chemosensitivity in Breast Cancer

Fascia Suture Technique Is a Simple Approach to Reduce Postmastectomy Seroma Formation.

Efficacy of neoadjuvant chemotherapy and Annexin A3 expression in breast cancer.