Analysis of TLR2 in Primary Endocrine Resistant of Breast Cancer.

BACKGROUND: Previous clinical studies have suggested that Toll-like receptor (TLR)2 had predictive function for endocrine resistance in HER2-positive breast cancer (BCa). Nevertheless, it remains unclear whether TLR2 would relate to development of endocrine therapy resistance in triple-positive breast cancer (TPBC). METHODS: Bioinformatic analysis of TLR2 was carried out through a database. Ten tumor tissues were obtained from TPBC patients who underwent surgery, with five patients displaying primary resistance to tamoxifen (TAM) with the remaining 5 being sensitive. Different levels of proteins were identified through mass spectrometry analysis and confirmed through reverse transcription polymerase chain reaction (RT-PCR) and western blot. TAM-resistant cell lines (BT474-TAM) were established by continuous exposure to TAM, and TAM resistance was assessed via IC50. Additionally, TLR2 mRNA was analyzed through western blot and RT-PCR in BT474, BT474-TAM, MCF-7, and MCF10A cells. Furthermore, TLR2-specific interference sequences were utilized to downregulate TLR2 expression in BT474-TAM cells to elucidate its role in TAM resistance. RESULTS: TLR2 had a correlation with decreased relapse-free survival in BCa patients from the GSE1456-GPL96 cohort, and it was involved in cancer development predominantly mediated by MAPK and PI3K pathways. TLR2 protein expression ranked in the top 5 proteins within the TAM-resistant group, and was 1.9 times greater than that in the sensitive group. Additionally, TLR2 mRNA and protein expression increased significantly in the established TAM-resistant BT474/TAM cell lines. The sensitivity of TAM was restored upon TLR2 downregulation in BT474/TAM cells. CONCLUSIONS: TLR2 might have a therapeutic value as it was involved in the TAM resistance in TPBC, with potential to be a marker for primary endocrine resistance.

ETV5 transcriptionally activates TGFß1 and promotes cancer cell invasion and migration of NSCLC.

The morbidity and mortality of NSCLC remains high worldwide. However, the molecular mechanisms of NSCLC still largely unclear. Ets variant 5 (ETV5) is a transcription factor that found to be overexpressed in multiple cancers. However, the role of ETV5 in NSCLC remains unknown. We aim to explore the role and mechanisms of ETV5 in NSCLC development. The expression of ETV5 was evaluated in NSCLC tissues and cell lines. ETV5 overexpressing and downregulation cell lines were established according to the endogenous expression of ETV5. Functional studies were performed by transwell assay. The downstream targets of ETV5 were screened by PCR array and were confirmed by luciferase reporter assay. We found that overexpression of ETV5 indicates worse prognosis of NSCLC patients. Elevated ETV5 expression promotes NSCLC cell invasion and migration via transcriptional activates of TGFß1. Therefore, ETV5/TGFß signaling may serve as a therapeutic target for NSCLS patients.

Repression of linc01555 up-regulates angiomotin-p130 via the microRNA-122-5p/clic1 axis to impact vasculogenic mimicry-mediated chemotherapy resistance in small cell lung cancer.

Long non-coding ribonucleic acid 01555 (linc01555) is a brand-new long non-coding RNA (lncRNA) that acts a carcinogenic function in various cancers. However, its role in small cell lung cancer (SCLC) is uncertain. This research was to figure out the role of linc01555 in cisplatin (DDP) resistance of SCLC cells and its possible latent mechanism. After establishment of the resistant sub-strain H446/DDP or DMS-53/DDP, detection of linc01555, microRNA (miR)-122-5p and CLICl was done in the H446/DDP or DMS-53/DDP cell line. After intervention, cell biological functions were determined, as well as tube formation ability. The detection of angiomotin (Amot)-p130 and the validation of the regulatory mechanism were performed. Furthermore, tumor xenografts were applied in nude mice to evaluate the effect of linc01555 on DDP resistance in SCLC in vivo. Linc01555 was elevated in SCLC tissues and cells, and in H446/DDP cells or DMS-53/DDP vs. its parental cells; Restraining linc01555 or elevating miR-122-5p repressed the proliferation and metastasis of H446/DDP or DMS-53/DDP cells and vasculogenic mimicry (VM) formation. CLIC1 mediated miR-122-5p to influence the occurrence and development of SCLC. Linc01555 competitively combined with miR-122-5p, which targeted CLIC1. Refrained linc01555 elevated Amot-p130 via the miR-122-5p/CLIC1 axis. Reduced linc01555 refrained tumor growth and DDP resistance in vivo.In short, linc01555 may cause changes in DDP resistance via miR-122-5p/CLIC1 in SCLC. The finding may offer drug targets for SCLC resistance.

The regulatory roles of T helper cells in distinct extracellular matrix characterization in breast cancer.

Background: Tumors are characterized by extracellular matrix (ECM) remodeling and stiffening. The ECM has been recognized as an important determinant of breast cancer progression and prognosis. Recent studies have revealed a strong link between ECM remodeling and immune cell infiltration in a variety of tumor types. However, the landscape and specific regulatory mechanisms between ECM and immune microenvironment in breast cancer have not been fully understood. Methods: Using genomic data and clinical information of breast cancer patients obtained from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, we conducted an extensive multi-omics analysis to explore the heterogeneity and prognostic significance of the ECM microenvironment. Masson and Sirius red staining were applied to quantify the contents of collagen in the ECM microenvironment. Tissue immunofluorescence (IF) staining was applied to identify T helper (Th) cells. Results: We classified breast cancer patients into two ECM-clusters and three gene-clusters by consensus clustering. Significant heterogeneity in prognosis and immune cell infiltration have been found in these distinct clusters. Specifically, in the ECM-cluster with better prognosis, the expression levels of Th2 and regulatory T (Treg) cells were reduced, while the Th1, Th17 and T follicular helper (Tfh) cells-associated activities were significantly enhanced. The correlations between ECM characteristics and Th cells infiltration were then validated by clinical tissue samples from our hospital. The ECM-associated prognostic model was then constructed by 10 core prognostic genes and stratified breast cancer patients into two risk groups. Kaplan-Meier analysis showed that the overall survival (OS) of breast cancer patients in the high-risk group was significantly worse than that of the low-risk group. The risk scores for breast cancer patients obtained from our prognostic model were further confirmed to be associated with immune cell infiltration, tumor mutation burden (TMB) and stem cell indexes. Finally, the half-maximal inhibitory concentration (IC50) values of antitumor agents for patients in different risk groups were calculated to provide references for therapy targeting distinct ECM characteristics. Conclusion: Our findings identify a novel strategy for breast cancer subtyping based on the ECM characterization and reveal the regulatory roles of Th cells in ECM remodeling. Targeting ECM remodeling and Th cells hold potential to be a therapeutic alternative for breast cancer in the future.

Construction of a Prognostic Nomogram Model for Patients with Mucinous Breast Cancer.

Objective: The objective of the study is to develop a nomogram for estimating three- and five-year survival rates in mucinous breast cancer patients. Methods: Between 2010 and 2016, the National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) were searched as a data source for patients associated with mucinous breast cancer (MBC). A total of 3964 patients were recruited after screening. The multivariate Cox model and the univariate Kaplan-Meier (KM) approach were employed to evaluate the independent prognostic markers, followed by developing a nomogram for estimating three- and five-year survival rates in MBC patients. Consequently, the consistency index (C-index) was employed to assess the predictive accuracy of the generated nomogram. Results: Age, race, T stage, M stage, surgery, and radiotherapy were all independent predictive biomarkers for the MBC patients (P < 0.05). The nomogram was finally developed based on the underlined factors. Furthermore, the C-index of 0.803 and reliable calibration curves were obtained in the nomogram's assessment. Conclusions: In patients with mucinous breast cancer, the proposed nomogram provides a viable tool for accurate prognostic prediction. In clinical practice, it could serve as a personalized diagnosis tool, estimate prognosis, and help in suggesting treatment plans for patients with MBC.

Neoantigen vaccine and neoantigen-specific cell adoptive transfer therapy in solid tumors: Challenges and future directions.

The phenomenon of tumor hierarchy and genetic instability can be explained by the "two-hits theory" and results in the occurrence of many somatic mutations. The expression of nonsynonymous mutations results in the production of mutant proteins from tumor cells, namely tumor-specific antigens called neoantigens. Because neoantigens do not exist in healthy cells, they have the potential to stimulate antitumor immune responses by CD4+ and CD8+ T-cell activation without jeopardizing normal tissues. Immunotherapy has reshaped the cancer treatment paradigm in recent decades with the introduction of immune-checkpoint blockade therapy and transgenic T-cell receptor/chimeric antigen receptor T cells. However, these strategies performed poorly in solid tumors because of the obstacles of the immunosuppressive microenvironment caused by regulatory T cells and other suppressor cells. Therefore, other immunotherapeutic strategies are under development, such as personalized vaccines, to trigger de novo T-cell responses against neoantigens and lead to the amplification of tumor-specific T-cell subclones. Neoantigen epitope prediction algorithms have enabled the detection of neoantigens and the creation of tailored neoantigen vaccines as a result of the fast development of next-generation sequencing and cancer bioinformatics. Here we provide an overview of the current neoantigen cancer vaccines and adoptive T-cell transfer therapy with neoantigen-specific lymphocytes. We also discuss the challenges in developing neoantigen-targeted immunotherapeutic strategies for cancer.

Angiomotin-p130 inhibits vasculogenic mimicry formation of small cell lung cancer independently of Smad2/3 signal pathway.

Lung cancer, the most concerning malignancy worldwide and one of the leading causes of cancer-related deaths. Growing evidence indicates that Angiomotin (Amot)-p130 plays an important role in types of cancer, including breast cancer and gastric cancer. Moreover, evidence suggested that the low Amot-p130 expression correlates with the poor prognosis of lung cancer patients, however, the role and mechanism of Amot-p130 in lung cancer is still unclear. In this study, we showed that Amot-p130 expression was reduced in lung cancer tissues, compared with the adjacent para-carcinoma tissues. In addition, we observed that the reduced expression of Amot-p130 was associated with vasculogenic mimicry (VM) channels formation in lung cancer tissues. Amot-p130 expression was differently expression in lung cancer cell line H446, H1688 and H2227 compared with the normal human lung cells HFL1. To clarify the role of Amot-p130 in lung cancer, we constructed the Amot-p130 expressing H446 cells and Amot-p130 silencing H1299 cells. We confirmed that Amot-p130 overexpression inhibited the migration and invasion of lung cancer cells, whereas its silence promoted cell migration and invasion. Interestingly, we also found that Amot-p130 overexpression suppressed VM tube formation in H446 cells, while its knockdown promoted VM tube formation in H2227 cells. Further studies suggested that Amot-p130 plays roles in M tube formation of lung cancer cell V are independent on smad2/3 signaling pathway. Finally, inoculation of Amot-p130 expressing H446 cells and Amot-p130 silencing H1299 cells into nude mice suppressed tumor growth, when compared with the control group. Based on these results, Amot-p130 serves as a possible diagnostic and therapeutic target in lung cancer patients, and may be an effective mediator of VM formation in lung cancer.

A nomogram for predicting survival in patients with de novo metastatic breast cancer: a population-based study.

BACKGROUND: 5-10% of patients are diagnosed with metastatic breast cancer (MBC) at the initial diagnosis. This study aimed to develop a nomogram to predict the overall survival (OS) of these patients. METHODS: de novo MBC patients diagnosed in 2010-2016 were identified from the Surveillance, Epidemiology, and End Results (SEER) database. They were randomly divided into a training and a validation cohort with a ratio of 2:1. The best subsets of covariates were identified to develop a nomogram predicting OS based on the smallest Akaike Information Criterion (AIC) value in the multivariate Cox models. The discrimination and calibration of the nomogram were evaluated using the Concordance index, the area under the time-dependent receiver operating characteristic curve (AUC) and calibration curves. RESULTS: In this study, we included 7986 patients with de novo MBC. The median follow-up time was 36 months (range: 0-83 months). Five thousand three-hundred twenty four patients were allocated into the training cohort while 2662 were allocated into the validation cohort. In the training cohort, age at diagnosis, race, marital status, differentiation grade, subtype, T stage, bone metastasis, brain metastasis, liver metastasis, lung metastasis, surgery and chemotherapy were selected to create the nomogram estimating the 1-, 3- and 5- year OS based on the smallest AIC value in the multivariate Cox models. The nomogram achieved a Concordance index of 0.723 (95% CI, 0.713-0.733) in the training cohort and 0.719 (95% CI, 0.705-0.734) in the validation cohort. AUC values of the nomogram indicated good specificity and sensitivity in the training and validation cohort. Calibration curves showed a favorable consistency between the predicted and actual survival probabilities. CONCLUSION: The developed nomogram reliably predicted OS in patients with de novo MBC and presented a favorable discrimination ability. While further validation is needed, this may be a useful tool in clinical practice.

RP11­284F21.9 promotes lung carcinoma proliferation and invasion via the regulation of miR­627­3p/CCAR1.

Lung carcinoma is a prominent cause of mortality among patients with cancer. Previous studies have reported the vital role of long non­coding RNAs (lncRNAs) in the malignant progression of lung cancer. lncRNA RP11­284F21.9 was originally identified to be expressed in lung carcinoma, but its specific function remains unknown. Therefore, the present study aimed to elucidate the role of lncRNA RP11­284F21.9 in lung carcinoma progression. The expression of RP11­284F21.9 in lung cell lines and tissues was measured using reverse transcription­quantitative PCR. The endogenous expression of RP11­284F21.9 was silenced using RNA interference, and cell viabilities were measured with a Cell Counting Kit­8 assay. The invasion and apoptosis of cells were determined via Transwell assays and flow cytometry, respectively. The protein expression levels were measured by western blotting. An increased expression of RP11­284F21.9 was identified in both lung carcinoma tissues and cells. Knockdown of RP11­284F21.9 in lung carcinoma cells inhibited cell proliferation and invasion, but promoted cell apoptosis. The present study identified the existence of a direct interaction between RP11­284F21.9 and microRNA (miRNA/miR)­627­3p. Mechanistically, it was demonstrated that RP11­284F21.9 promoted the proliferation and invasiveness of lung carcinoma cells, in part, via the regulation of miR­627­3p. Furthermore, cell division cycle and apoptosis regulator 1 (CCAR1) was identified as a target gene of miR­627­3p. The in vivo tumor growth assay also demonstrated that the knockdown of RP11­284F21.9 suppressed tumor growth, upregulated miR­627­3p and downregulated CCAR1 in the xenograft model of nude mice. Thus, the present findings indicated the tumor promoting functions of RP11­284F21.9 in the progression of lung carcinoma, and provided a novel lncRNA/miRNA axis as a target for the management of lung cancer.

Thalidomide suppresses breast cancer tumor growth by inhibiting tumor-associated macrophage accumulation in breast tumor-bearing mice.

we aimed to explore the role of thalidomide in breast cancer by using a mouse 4T1 breast tumor model. A tumor model was established by injecting logarithmic-phase 4T1 cells into the mammary fat pat.Tumor growth was monitored every day and tumor size was measured periodically. Which were performed to determine the cytokine and related gene mRNA expression, the cytokine production and protein expression, check the vessel formation and necrosis, the CD31 expression,the expression of CD31, F4/80 and CD206,staining the digested cells with F4/80, cd45 and CD11b to determine the M2 type macrophages accumulation by qRT-PCR, Cytokine antibody array, HE staining, Immunohistochemistry, Immunostaining, Flow cytometry, respectively. In the current study, Our results indicated that thalidomide significantly inhibited tumor growth in the mouse model by inhibiting angiogenesis and promoting the necrosis of tumor cells in tumor tissues. Moreover, immunostaining and flow cytometry results demonstrated that M2-type tumor-associated macrophage accumulation and infiltration were profoundly inhibited upon treatment with thalidomide. In addition, thalidomide treatment also regulated cytokine production by inhibiting the production of angiogenesis-related cytokines, such as G-CSF, VEGF-B, VEGFR1, VEGFR3 and IL-10. In conclusion, our studies explored the antitumor effect of thalidomide in a breast tumor model and uncovered that thalidomide inhibited breast tumor growth by inhibiting angiogenesis as a result of reducing TAM accumulation and infiltration and inhibiting angiogenesis-related cytokine production.

Clinicopathological features, survival and risk in breast cancer survivors with thyroid cancer: an analysis of the SEER database.

BACKGROUND: The co-occurrence of breast cancer (BC) and thyroid cancer (TC) has been mentioned for several years, researchers observed an increased risk of BC patients to develop TC, but few researches concern about the features, survival of BC patients followed by TC and the influent factors of the incidence risk. The present study aimed to estimate the clinicopathological features, survival of BC survivors who had primary TC and the predictive factors on the risk of BC patients to develop TC. METHODS: Women diagnosed with BC between 1992 and 2011, and then developed TC from the Surveillance, Epidemiology, and End Results Database were included. Standardized incidence ratios (SIRs) was used to perform multiple primary analyses, generated from the multiple primary-SIR program in SEER*Stat. RESULTS: A total of 842 BC then TC patients were included, the median age was 54 years. Additionally, 78.39% were white, 60.45% had T1 cancer, 62.47% had negative lymph nodes, and more than 75% had infiltrating duct carcinoma, 5-year survival rate was 95.4%. Compared with BC only patients, they were younger, had smaller tumor size and a relatively better prognosis. The risk of developing TC was higher in BC patients than in the general population (SIR 1.22, 95% CI [1.14, 1.31]), especially within 3 years. The influent factors of SIR were black race, BC tumor site, grade and ER/PR positive expression. CONCLUSIONS: BC patients followed by TC had its particular clinicopathological features. Compared with the features and survival of BC only patients, they were younger, had a smaller tumor size and a relatively better prognosis. Furthermore, BC patients had a high risk of developing TC, especially within 3 years. Black women, primary tumor located in an upper-outer, central, or overlapping site, high grade tumor and with positive hormone receptor expression were predictive factors to develop TC.

Tumor vasculature remolding by thalidomide increases delivery and efficacy of cisplatin.

BACKGROUND: A promising strategy to overcome the chemoresistance is the tumor blood vessel normalization, which restores the physiological perfusion and oxygenation of tumor vasculature. Thalidomide (Thal) has been shown to increase the anti-tumor effect of chemotherapy agents in solid tumors. However, it is not yet known whether the synergistic effect of Thal combined with other cytotoxic drugs is attributable to tumor vascular normalization. METHODS: We used two homograft mice models (4 T1 breast tumor model and CT26 colorectal tumor model) to investigate the effect of Thal on tumor growth, microvessel density, vascular physiology, vascular maturity and function, drug delivery and chemosensitivity. Immunofluorescence, immunohistochemistry and scanning electron microscopy were performed to determine the vessel changes. Protein array assay, qPCR and western blotting were used to detect the molecular mechanism by which Thal regulates tumor vascular. RESULTS: Here we report that Thal potently suppressed tumor growth, angiogenesis, hypoxia, and vascular permeability in animal models. Thal also induced a regular monolayer of endothelial cells in tumor vessels, inhibiting vascular instability, and normalized tumor vessels by increasing vascular maturity, pericyte coverage and endothelial junctions. The tumor vessel stabilization effect of Thal resulted in a decrease in tumor vessel tortuosity and leakage, and increased vessel thickness and tumor perfusion. Eventually, the delivery of cisplatin was highly enhanced through the normalized tumor vasculature, thus resulting in profound anti-tumor and anti-metastatic effects. Mechanistically, the effects of Thal on tumor vessels were caused in part by its capability to correct the imbalance between pro-angiogenic factors and anti-angiogenic factors. CONCLUSIONS: Our findings provide direct evidence that Thal remodels the abnormal tumor vessel system into a normalized vasculature. Our results may lay solid foundation for the development of Thal as a novel candidate agent to maximize the therapeutic efficacy of chemotherapeutic drugs for solid tumors.

Comparative Analysis of Outcomes and Clinicopathological Characteristics of Synchronous and Metachronous Contralateral Breast Cancer: A Study of the SEER Database.

PURPOSE: Numerous previous studies have reported inconsistent results about the differences between synchronous contralateral breast cancer (sCBC) and metachronous contralateral breast cancer (mCBC). This study aimed to compare the clinical characteristics and outcomes between sCBC and mCBC and determine predictive factors for the survival of sCBC and mCBC patients. METHODS: Using the Surveillance, Epidemiology, and End Results Program database, we identified sCBC or mCBC patients from 2000 to 2010. The Kaplan-Meier method and Cox proportional hazards regression analysis were used to analyze overall survival and breast cancer-specific survival (BCSS) rates of sCBCs and mCBCs, respectively. RESULTS: Overall, 14,057 sCBC (n = 8,139, 57.9%) and mCBC (n = 5,918, 42.1%) patients were included. The first tumors of sCBC were more likely to have higher stage and more lymph and distant metastases, whereas those of mCBC were more often infiltrating ductal carcinoma (IDC), had localized stage, were estrogen receptor (ER) and progesterone receptor (PR) negative, and had less axillary nodal involvement. The second tumors of mCBC tended to be IDC and have higher grade, adverse stage, ER and PR-negativity; and more axillary nodal involvement, compared to the second tumors of sCBC. mCBC patients had significantly favorable 5-year BCSS but worse long-term BCSS compared with sCBC patients. Moreover, subgroup analysis revealed no significant difference of BCSS between sCBC and mCBC among patients aged 18-60 years. Multivariate analysis indicated that age, grade, and stage of 2 tumors; surgery for second tumor; and ER status of the second tumor were independent prognostic factors for BCSS of contralateral breast cancer (CBC). CONCLUSION: The characteristics and outcomes of sCBCs and mCBCs were substantially different. sCBC and mCBC patients may have different prognosis, and the prognosis of CBC depends on the first and second tumors.

Metformin inhibits metastatic breast cancer progression and improves chemosensitivity by inducing vessel normalization via PDGF-B downregulation.

BACKGROUND: Vascular maturity and functionality are closely associated with tumor progression and chemosensitivity. The antidiabetic agent metformin has shown its ability to inhibit tumor angiogenesis in metastatic breast cancer models. However, it remains unclear if or how metformin remodels the abnormal vasculature of metastatic breast cancer, while inhibiting angiogenesis. METHODS: Metastatic breast cancer models were constructed to compare microvessel density (MVD), vascular maturity and function, lung metastasis and chemosensitivity in metformin-treated or untreated mice. Protein array assay and transcriptome sequencing were performed for genetic screening. Lentiviral shRNA-PDGF-B transfection was used for observing the contribution of PDGF-B knockdown to metformin's vascular effects. RESULTS: Metastatic breast cancers were characterized by an excessively angiogenic, immature and morphologically abnormal vasculature. Compared to control, metformin significantly reduced MVD, leakage and hypoxia, and increased vascular mural cells coverage and perfusion, namely, "vessel normalization". Metformin at human blood concentrations had no direct effect on the migration and proliferation of cancer cells. Based on that, reduced lung metastasis of the primary tumor and improved chemosensitization by metformin were assumed to be mediated via metformin's vascular effects. Further results of genetic screening and in vivo experiments showed that the downregulation of platelet-derived growth factor B (PDGF-B) greatly contributed to the metformin-induced vessel normalization. CONCLUSIONS: These findings provide pre-clinical evidences for the vascular mechanism of metformin-induced metastasis inhibition and the chemosensitization of metastatic breast cancers.

Angiomotin-p130 inhibits ß-catenin stability by competing with Axin for binding to tankyrase in breast cancer.

Growing evidence indicates that Angiomotin (Amot)-p130 and Amot-p80 have different physiological functions. We hypothesized that Amot-p130 is a tumor suppressor gene in breast cancer, in contrast with the canonical oncogenicity of Amot-p80 or total Amot. To clarify the role of Amot-p130 in breast cancer, we performed real-time quantitative PCR, western blotting, flow cytometry, microarray, immunofluorescence, immunoprecipitation, and tumor sphere-formation assays in vitro, as well as tumorigenesis and limited-dilution analysis in vivo. In this study, we showed that Amot-p130 inhibited the proliferation, migration, and invasion of breast cancer cells. Interestingly, transcriptional profiles indicated that genes differentially expressed in response to Amot-p130 knockdown were mostly related to ß-catenin signaling in MCF7 cells. More importantly, most of the downstream partners of ß-catenin were associated with stemness. In a further validation, Amot-p130 inhibited the cancer stem cell potential of breast cancer cells both in vitro and in vivo. Mechanistically, Amot-p130 decreased ß-catenin stability by competing with Axin for binding to tankyrase, leading to a further inhibition of the WNT pathway. In conclusions, Amot-p130 functions as a tumor suppressor gene in breast cancer, disrupting ß-catenin stability by competing with Axin for binding to tankyrase. Amot-p130 was identified as a potential target for WNT pathway-targeted therapies in breast cancer.

Colorectal cancer-derived small extracellular vesicles establish an inflammatory premetastatic niche in liver metastasis.

Liver metastases develop in more than half of the patients with colorectal cancer (CRC) and are associated with a poor prognosis. The factors influencing liver metastasis of CRC are poorly characterized, but this information is urgently needed. We have now discovered that small extracellular vesicles (sEVs; exosomes) derived from CRC can be specifically targeted to liver tissue and induce liver macrophage polarization toward an interleukin-6 (IL-6)-secreting proinflammatory phenotype. More importantly, we found that microRNA-21-5p (miR-21) was highly enriched in CRC-derived sEVs and was essential for creating a liver proinflammatory phenotype and liver metastasis of CRC. Silencing either miR-21 in CRC-sEVs or Toll-like receptor 7 (TLR7) in macrophages, to which miR-21 binds, abolished CRC-sEVs' induction of proinflammatory macrophages. Furthermore, miR-21 expression in plasma-derived sEVs was positively correlated with liver metastasis in CRC patients. Collectively, our data demonstrate a pivotal role of CRC-sEVs in promoting liver metastasis by inducing an inflammatory premetastatic niche through the miR-21-TLR7-IL-6 axis. Thus, sEVs-miR-21 represents a potential prognostic marker and therapeutic target for CRC patients with liver metastasis.

AmotP130 regulates Rho GTPase and decreases breast cancer cell mobility.

Angiomotin (Amot) is a newly discovered, multifunctional protein that is involved in cell migration and angiogenesis. However, the role of its isoform, AmotP130, in the regulation of cytoskeleton and metastasis of breast cancer, is unclear. The aim of this study was to investigate the role of AmotP130 in the reorganization of the actin cytoskeleton and the changes of morphology in breast cancer cells through the Rho pathway that influences the invasion and migration of cells. The results suggested that AmotP130 suppressed the invasion ability through remodelling the cytoskeleton of breast cancer cells, including the actin fibre organization and focal adhesion protein turnover. Global transcriptome changes in breast cancer cells following knockdown of AmotP130 identified pathways related with the cytoskeleton and cell motility that involved the Rho GTPase family. From database analyses, changes in the Rho GTPase family of proteins were identified as possible prognostic factors in patients with breast cancer. We have been suggested that AmotP130 suppressed the invasion ability through remodelling of the cytoskeleton of breast cancer cells, involving regulation of the Rho pathway. The cytoskeleton-related pathway components may provide novel, clinically therapeutic targets for breast cancer treatment.

Clinicopathological features and survival of early stage breast cancer in northwest China: A population-based retrospective study of 1287 patients.

BACKGROUND: Breast cancer (BC) displays different clinicopathological features and outcomes based on patient age, molecular subtype, and treatment. However, such features in BC patients in northwest China are unclear. This study investigated the clinicopathological features and overall survival (OS) of early stage BC patients using a population-based study. METHODS: Patients who were newly diagnosed with BC at the First Affiliated Hospital of Xi'an Jiaotong University between January 2001 and June 2012 were included. Clinicopathological features and OS were assessed. RESULTS: The median age of 1287 patients was 50 years, with an average tumor size of 2.65 cm. Additionally, 42.7% were luminal A, 25.6% luminal B, 9.3% Her2 overexpression, and 17.7% triple negative. The cut-off age was 35 years, and young patients (< 35) tended to have larger tumors, ≥ 4 positive lymph nodes, grade 2 or 3 histology, non-luminal types, high Ki67, and poor outcomes. Patients with luminal A tumors showed moderate features: 50.6% had tumors < 2 cm, 56.7% had negative lymph nodes. Patients with Her2 overexpression tumors showed aggressive features and the poorest survival (5-year OS 67.6%). Patients with triple negative tumors were the youngest (average 48.4 years), but had the largest proportion of grade 3 histology and poor outcomes. CONCLUSION: Our results are consistent with those in other provinces in China, but showed an earlier age at diagnosis and more aggressive pathological features compared to developed countries. Additionally, each molecular subtype showed specific features and different survival outcomes.

The risk and survival outcome of subsequent primary colorectal cancer after the first primary colorectal cancer: cases from 1973 to 2012.

BACKGROUND: Among colorectal cancer (CRC) survivors, how the prior tumor location affects the risk of subsequent primary colorectal cancer (SPCRC) and the outcome of those suffering from SPCRC remain unknown. METHODS: CRC cases diagnosed from 1973 to 2012 were screened for SPCRC development using the Surveillance, Epidemiology, and End Results database. The relative risk of SPCRC was estimated using the standardized incidence ratio. Survivals were analyzed using the Kaplan-Meier and Cox regression model. RESULTS: The overall risk of SPCRC increased by 27% in CRC survivors compared to that of the general population. The risk increased in patients with both prior right colon cancer (RCC) and left colon cancer (LCC), and was concentrated in the first 5 years after the prior diagnosis, and among young patients. Among the 6701 SPCRC patients identified, patients with prior RCC were more likely to be elderly, female, and with more low or undifferentiated disease than those with prior LCC or rectal cancer (ReC). The overall survivals differed by both prior tumor location (P < 0.0001) and age (P < 0.0001), and the difference by tumor location remained significant when adjusted or stratified by any other potential prognostic factor except age. The cancer specific survivals differed by age (P < 0.0001) rather than by prior tumor location (P = 0.455). CONCLUSIONS: The overall risk of SPCRC increased among patients with both prior RCC and LCC, but not among those with ReC. The different survival outcomes in CRC survivors suffering from SPCRC were largely explained by the patient age but not by the prior tumor location.