Cancer tissues consist of cancer cells, surrounding stromal cells and the extracellular matrix. Cancer‐associated fibroblasts (CAF) are one of the key components of stromal cells. CAF have a great ...impact on the behavior of cancer cells, including proliferation, invasion, metastasis and chemoresistance in many ways. However, the underlying mechanism had not been fully elucidated. In this study, we investigated the role of CAF in cisplatin resistance of lung cancer cells. By using conditioned medium from CAF (CAF‐CM), we found that CAF decreased the sensitivity of lung cancer cells to cisplatin. RNA sequencing results showed that CAF expressed a higher level of Annexin A3 (ANXA3) than normal fibroblasts (NF), and CAF‐CM incubation increased the ANXA3 level in lung cancer cells. Overexpression of ANXA3 in lung cancer cells increased cisplatin resistance and activated c‐jun N‐terminal kinase (JNK), whereas knockdown of ANXA3 increased cisplatin sensitivity. Further study showed that CAF‐CM enhanced cisplatin resistance by inhibiting cisplatin‐induced apoptosis, determined by repression of caspase‐3 and caspase‐8, through activation of the ANXA3/JNK pathway. Conversely, suppression of JNK activation by specific inhibitor retarded the effect of CAF‐CM and ANXA3 on cisplatin sensitivity. Taken together, our study demonstrated that CAF potentiated chemoresistance of lung cancer cells through a novel ANXA3/JNK pathway both in vitro and in vivo, suggesting ANXA3 could be a potential therapeutic target for the treatment of chemoresistant cancer.
Cancer‐associated fibroblasts decreased the sensitivity of lung cancer cells to cisplatin. CAF expressed higher level of ANXA3 than normal fibroblasts (NF), and CAF‐CM incubation increased the ANXA3 level in lung cancer cells. CAF potentiated chemoresistance of lung cancer cells through a novel ANXA3/JNK pathway both in vitro and in vivo.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Tumor progression requires the communication between tumor cells and tumor microenvironment (TME). Cancer-associated fibroblasts (CAFs) are major components of stromal cells. CAFs contribute to ...metastasis process through direct or indirect interaction with tumor cells; however, the underlying mechanism is largely unknown. Here, we reported that autophagy was upregulated in lung cancer-associated CAFs compared to normal fibroblasts (NFs), and autophagy was responsible for the promoting effect of CAFs on non-small cell lung cancer (NSCLC) cell migration and invasion. Inhibition of CAFs autophagy attenuated their regulation on epithelial-mesenchymal transition (EMT) and metastasis-related genes of NSCLC cells. High mobility group box 1 (HMGB1) secreted by CAFs mediated CAFs' effect on lung cancer cell invasion, demonstrated by using recombinant HMGB1, HMGB1 neutralizing antibody, and HMGB1 inhibitor glycyrrhizin (GA). Importantly, the autophagy blockade of CAFs revealed that HMGB1 release was dependent on autophagy. We also found HMGB1 was responsible, at least in part, for autophagy activation of CAFs, suggesting CAFs remain active through an autocrine HMGB1 loop. Further study demonstrated that HMGB1 facilitated lung cancer cell invasion by activating the NFκB pathway. In a mouse xenograft model, the autophagy specific inhibitor chloroquine abolished the stimulating effect of CAFs on tumor growth. These results elucidated an oncogenic function for secretory autophagy in lung cancer-associated CAFs that promotes metastasis potential, and suggested HMGB1 as a novel therapeutic target.
Recent studies indicate that cancer-associated fibroblasts (CAFs) are involved in tumor growth, invasion and metastasis, however, the underling mechanisms remain unclear. In the present study, we ...investigated the role of CAFs on the metastatic potential of lung cancer cells. The stromal fibroblasts we isolated from lung cancer tissues presented CAFs characteristics with high levels of α-smooth muscle actin (α-SMA) and fibroblast-activating protein (FAP). Our data showed that the conditioned medium from cultured CAFs (CAF-CM) dramatically enhanced migration and invasion of lung cancer cells. CAF-CM induced epithelial-mesenchymal transition (EMT) by regulating the expression of EMT-associated markers E-cadherin and vimentin, and also modulated metastasis-related genes MMP-2 and VEGF both
and
. Further mechanistic studies demonstrated that CAFs enhanced the metastatic potential of lung cancer cells by secreting IL-6, subsequently activating of JAK2/STAT3 signaling pathway. Additionally, the inhibition of IL-6/STAT3 signaling pathway by IL-6 neutralizing antibody or specific inhibitors of JAK2/STAT3 reversed CAF-CM induced EMT and migration of lung cancer cells. Taken together, these findings revealed a novel mechanism that CAFs induced EMT and promoted metastasis of lung cancer cells through the IL-6/STAT3 signaling pathway.
MAPK signaling inhibitor (MAPKi) therapies show limited efficacy for advanced thyroid cancers despite constitutive activation of the signaling correlates with disease recurrence and persistence. ...Understanding how BRAF pathway stimulates tumorigenesis could lead to new therapeutic targets. Here, through genetic and pathological approaches, we demonstrate that BRAF
promotes thyroid cancer development by increasing myeloid-derived suppressor cells (MDSCs) penetrance. This BRAF
-induced immune suppression involves re-activation of the developmental factor TBX3, which in turn up-regulates CXCR2 ligands in a TLR2-NFκB dependent manner, leading to MDSCs recruitment into the tumor microenvironment. CXCR2 inhibition or MDSCs repression improves MAPKi therapy effect. Clinically, high TBX3 expression correlates with BRAF
mutation and increased CXCR2 ligands, along with abundant MDSCs infiltration. Thus, our study uncovers a BRAF
-TBX3-CXCLs-MDSCs axis that guides patient stratification and could be targeted to improve the efficacy of MAPKi therapy in advanced thyroid cancer patients.
Most lung cancer patients die of metastasis. Recent studies have indicated that dysregulated microRNAs (miRNAs) are involved not only in tumorigenesis, but also in metastasis. In the present study, ...we found that over-expression of miR-26a-5p potentiated the migration and invasion of lung cancer cells evidenced by wound healing assay and transwell assay, and metastasis-related genes MMP-9 and CD44 were up-regulated. We identified integrin-beta8 (ITGβ8) as a novel target of miR-26a, and ITGβ8 expression was negatively correlated with miR-26a-5p expression in lung cancer specimens. Mechanism study showed that miR-26a-5p enhanced lung cancer cell metastasis via activation of Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway, and ITGβ8 mediated the activation of JAK2/STAT3 pathway by miR-26a-5p. By using in vivo imaging technology, we found that miR-26a-5p enhanced both tumor growth and metastasis in vivo; and activated JAK2/STAT3 pathway. Taken together, our results demonstrated that miR-26a-5p potentiated lung cancer cell metastasis via JAK2/STAT3 pathway by targeting ITGβ8. This finding provides insights into the mechanism underlying miRNAs regulation on lung cancer metastasis; and suggests miR-26a-5p as a therapeutic target for lung cancer treatment.
•90% of lung cancer patients die of metastasis.•miR-26a-5p enhances metastasis potential of lung cancer both in vitro and in vivo.•ITGβ8 is identified as a novel target of miR-26a-5p.•miR-26a-5p enhances lung cancer cell metastasis via activation of JAK2/STAT3 pathway.
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Phenethyl isothiocyanate (PEITC) is a natural compound abundant in cruciferous vegetables. PEITC possesses anti‐tumor effect in various human malignances. Our previous study has shown that benzyl ...isothiocyanates (BITC) induce autophagy in lung cancer cells. However, whether autophagy play a role in the inhibitory effect of PEITC on lung cancer metastasis is unclear. In this study, we found that PEITC suppressed migration and invasion of lung cancer cells by regulating MMP2. It also induced autophagy, evidenced by the formation of acidic vesicular organelles (AVOs), the punctate pattern of LC3, the accumulation of LC3‐II, and the expression of Beclin‐1. Inhibition of autophagy by 3‐MA and chloroquine (CQ) or knock down of Beclin‐1 enhanced PEITC‐caused metastasis inhibition. JAK2/STAT3 pathway was suppressed by PEITC, and further inhibited by 3‐MA and CQ or Beclin‐1 knock down, as a result of decreased expression of p‐JAK2 and p‐STAT3. Blocking JAK2/STAT3 pathway by inhibitor AG490 and Stattic suppressed cell migration and decreased the expression of MMP2, MMP9, Twist, and c‐Myc. Further in vivo study showed that PEITC inhibited tumor growth, induced autophagy and suppressed JAK2/STAT3 pathway, and inhibitor CQ enhanced this effect. Taken together, our results demonstrate that PEITC inhibits metastasis potential of lung cancer cells, and induces autophagy. The autophagy induced by PEITC preserves metastasis potential of lung cancer cells, via activation of JAK2/STAT3 pathway. Inhibition of autophagy enhanced the inhibitory effect of PEITC on metastasis potential of lung cancer cells. Our finding suggests that targeting autophagy could be a promising strategy for anti‐metastasis therapies.
Full text
Available for:
BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Exosomes are nanoscale monolayer membrane vesicles that are actively endogenously secreted by mammalian cells. Currently, multifunctional exosomes with tumor-targeted imaging and therapeutic ...potential have aroused widespread interest in cancer research. Herein, we developed a multifunctional HEK-293T exosome-based targeted delivery platform by engineering HEK-293T cells to express a well-characterized exosomal membrane protein (Lamp2b) fused to the αv integrin-specific iRGD peptide and tyrosine fragments. This platform was loaded with doxorubicin (Dox) and labeled with radioiodine-131 (
I) using the chloramine-T method. iRGD exosomes showed highly efficient targeting and Dox delivery to integrin αvβ3-positive anaplastic thyroid carcinoma (ATC) cells as demonstrated by confocal imaging and flow cytometry in vitro and an excellent tumor-targeting capacity confirmed by single-photon emission computed tomography-computed tomography after labeling with
I in vivo. In addition, intravenous injection of this vehicle delivered Dox and
I specifically to tumor tissues, leading to significant tumor growth inhibition in an 8505C xenograft mouse model, while showing biosafety and no side effects. These as-developed multifunctional exosomes (denoted as Dox@iRGD-Exos-
I) provide novel insight into the current treatment of ATC and hold great potential for improving therapeutic efficacy against a wide range of integrin αvβ3-overexpressing tumors.
Full text
Available for:
IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Objective
Osseous metastasis (OM) is the second most common site of thyroid cancer distant metastasis and presents a poor prognosis. Accurate prognostic estimation for OM has clinical significance. ...Ascertain the risk factors for survival and develop an effective model to predict the 3-year, 5-year overall survival (OS) and cancer-specific survival (CSS) for thyroid cancer patients with OM.
Methods
We retrieved the information of patients with OMs between 2010 and 2016 from the Surveillance, Epidemiology, and End Result Program. The Chi-square test, and univariate and multivariate Cox regression analyses were performed. Four machine learning (ML) algorithms, which were most commonly used in this field, were applied.
Result
A total of 579 patients having OMs were eligible. Advanced age, tumor size ≥ 40 mm, combined with other distant metastasis were associated with worse OS in DTC OMs patients. Radioactive iodine (RAI) significantly improved CSS in both males and females. Among four ML models logistic regression, support vector machines, extreme gradient boosting, and random forest (RF), RF had the best performance area under the receiver-operating characteristic curve: 0.9378 for 3-year CSS, 0.9105 for 5-year CSS, 0.8787 for 3-year OS, 0.8909 for 5-year OS. The accuracy and specificity of RF were also the best.
Conclusions
RF model shall be used to establish an accurate prognostic model for thyroid cancer patients with OM, not only from the SEER cohort but also intended for all thyroid cancer patients in the general population, which may be applicable in clinical practice in the future.
Full text
Available for:
EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
PDF
