Stresses in the metastatic cascade: molecular mechanisms and therapeutic opportunities.

Metastasis is the ultimate "survival of the fittest" test for cancer cells, as only a small fraction of disseminated tumor cells can overcome the numerous hurdles they encounter during the transition from the site of origin to a distinctly different distant organ in the face of immune and therapeutic attacks and various other stresses. During cancer progression, tumor cells develop a variety of mechanisms to cope with the stresses they encounter, and acquire the ability to form metastases. Restraining these stress-releasing pathways could serve as potentially effective strategies to prevent or reduce metastasis and improve the survival of cancer patients. Here, we provide an overview of the tumor-intrinsic, microenvironment- and treatment-induced stresses that tumor cells encounter in the metastatic cascade and the molecular pathways they develop to relieve these stresses. We also summarize the preclinical and clinical studies that evaluate the potential therapeutic benefit of targeting these stress-relieving pathways.

ASB13 inhibits breast cancer metastasis through promoting SNAI2 degradation and relieving its transcriptional repression of YAP.

Transcription factor SNAI2 plays key roles during development and has also been known to promote metastasis by inducing invasive phenotype and tumor-initiating activity of cancer cells. However, the post-translational regulation of SNAI2 is less well studied. We performed a dual-luciferase-based, genome-wide E3 ligase siRNA library screen and identified ASB13 as an E3 ubiquitin ligase that targets SNAI2 for ubiquitination and degradation. ASB13 knockout in breast cancer cells promoted cell migration and decreased F-actin polymerization, while overexpression of ASB13 suppressed lung metastasis. Furthermore, ASB13 knockout decreased YAP expression, and such regulation is dependent on an increased protein level of SNAI2, which in turn represses YAP transcription. YAP suppresses tumor progression in breast cancer, as YAP knockout increases tumorsphere formation, anchorage-independent colony formation, cell migration in vitro, and lung metastasis in vivo. Clinical data analysis reveals that ASB13 expression is positively correlated with improved overall survival in breast cancer patients. These findings establish ASB13 as a suppressor of breast cancer metastasis by promoting degradation of SNAI2 and relieving its transcriptional repression of YAP.

Deubiquitinase USP20 promotes breast cancer metastasis by stabilizing SNAI2.

SNAI2/SLUG, a metastasis-promoting transcription factor, is a labile protein that is degraded through the ubiquitin proteasome degradation system. Here, we conducted comprehensive gain- and loss-of-function screens using a human DUB cDNA library of 65 genes and an siRNA library of 98 genes, and identified USP20 as a deubiquitinase (DUB) that regulates SNAI2 ubiquitination and stability. Further investigation of USP20 demonstrated its function in promoting migration, invasion, and metastasis of breast cancer. USP20 positively correlates with SNAI2 protein level in breast tumor samples, and higher USP20 expression is associated with poor prognosis in ER- breast cancer patients.

Transforming growth factor ß1 signaling coincides with epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis in mice.

STUDY QUESTION: Do platelets have any role in the development of adenomyosis? SUMMARY ANSWER: Activated platelets coincide with the release of transforming growth factor (TGF)-ß1 and induction of the TGF-ß/Smad signaling pathway as well as evidence of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT) in a mouse model of adenomyosis, resulting ultimately in fibrosis, as in adenomyosis. WHAT IS KNOWN ALREADY: Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis, but this was based primarily on cross-sectional observation. It is unclear as to whether adenomyotic lesions and their microenvironment have the machinery to promote EMT and FMT, resulting ultimately in fibrosis. There has not been any published study on the role of platelets in the development of adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which implicates the involvement of platelets and constitutes an environment conducive for fibrogenesis. STUDY DESIGN, SIZE, DURATION: Adenomyosis was induced in 28 female ICR mice by neonatal dosing of tamoxifen. Another 32 were neonatally dosed without tamoxifen. These mice were sacrificed serially and their tissue samples were subsequently evaluated. PARTICIPANTS/MATERIALS, SETTING, METHODS: Female ICR mice with and without induced adenomyosis were sacrificed in batch at 5, 10, 15, 42 and 60 days of age. The depth of myometrial infiltration of endometrial tissues was assessed and immunohistochemistry analysis of biomarkers of EMT and FMT, as well as TGF-ß1, phosphorylated Smad3 (p-Smad3) and markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits was performed in ectopic (for adenomyotic mice) and eutopic (controls) endometrial tissue samples. Masson trichrome and Van Gieson stainings were performed to quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. MAIN RESULTS AND THE ROLE OF CHANCE: While TGF-ß1 immunoreactivity was consistently low in control endometrium, its level was increased dramatically starting from Day 10, along with the extent of platelet aggregation. Staining for TGF-ß1 and p-Smad3 increased progressively as adenomyosis progressed, along with markers for proliferation, angiogenesis and ECM deposits. Consistently, staining of vimentin (a marker for stromal or mesenchymal cells) was also increased while that of E-cadherin (a marker for epithelial cells) was reduced. PR-B staining also decreased progressively. Starting from Day 42, α-SMA staining, a marker for myofibroblasts, was elevated in lesions, while in control endometrium, it was negative. Concomitantly, the extent of fibrosis also was increased. LIMITATIONS, REASONS FOR CAUTION: This study is limited by the use of histochemistry and immunohistochemistry analyses only and the lack of intervention. WIDER IMPLICATIONS OF THE FINDINGS: Like their endometriotic counterpart, adenomyotic lesions and their microenvironment may contain all the necessary molecular machinery to promote fibrogenesis. Platelet-induced activation of the TGF-ß/Smad signaling pathway may be a driving force in EMT and FMT in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and as such, platelets play critical roles in the development of adenomyosis. It suggests the potential for the use of anti-platelet therapy in the treatment of adenomyosis, and also opens a new venue for developing novel biomarkers for diagnostic or prognostic purposes. STUDY FUNDING/COMPETING INTERESTS: Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

Corroborating evidence for platelet-induced epithelial-mesenchymal transition and fibroblast-to-myofibroblast transdifferentiation in the development of adenomyosis.

STUDY QUESTION: Do platelets play any role in the development of adenomyosis? SUMMARY ANSWER: As in endometriosis, adenomyotic lesions show significantly increased platelet aggregation, increased expression of transforming growth factor (TGF)-ß1, phosphorylated Smad3, markers of epithelial-mesenchymal transition (EMT) and fibroblast-to-myofibroblast transdifferentiation (FMT), and smooth muscle metaplasia (SMM), in conjunction with increased fibrosis as compared with normal endometrium. WHAT IS KNOWN ALREADY: Both EMT and FMT are known to play vital roles in fibrogenesis in general and in endometriosis in particular. EMT has been implicated in the development of adenomyosis. SMM is universally seen in endometriosis and also in adenomyosis, and is correlated positively with the extent of fibrosis. However, there has been no published study on the role of platelets in fibrogenesis in adenomyosis, even though adenomyotic lesions undergo repeated cycles of tissue injury and repair, which suggests the involvement of platelets and their possible roles in fibrogenesis. STUDY DESIGN, SIZE, DURATION: Cross-sectional studies of ectopic endometrial and control endometrial tissue samples from three sets of women with and without adenomyosis (n= 34 and 20, 12 and 10, and 8 and 8, respectively) were carried out from 2014 to 2015. PARTICIPANTS/MATERIALS, SETTING, METHODS: Immunohistochemistry analysis of ectopic endometrial tissues from women with (n= 34) and without (n= 20) adenomyosis with respect to biomarkers of EMT, FMT and highly differentiated smooth muscle cells as well as TGF-ß1, phosphorylated Smad3, markers of proliferation, angiogenesis and extracellular matrix (ECM) deposits. Masson trichrome staining, Van Gieson staining and Pico-Sirius staining were performed to evaluate and quantify the extent of fibrosis in lesions. Progesterone receptor isoform B (PR-B) staining also was performed. In addition, CD42b-positive platelets in ectopic (n= 12) and control (n= 10) endometrium were counted by confocal microscopy and compared. The protein expression levels of TGF-ß1 and phosphorylated Smad3 in both ectopic (n= 8) and control (n= 8) endometrium were measured by western blot analysis. Immunofluorescent staining of both platelets and hepatocyte growth factor (HGF) was also performed for adenomyotic tissue samples (n= 10). MAIN RESULTS AND THE ROLE OF CHANCE: Adenomyotic lesions had a significantly higher extent of platelet aggregation and increased staining for TGF-ß1 and phosphorylated Smad3 (both P-values <0.001 versus control). In addition, E-cadherin staining was decreased while vimentin staining in adenomyotic epithelial cells was increased, along with increased staining of proliferating cell nuclear antigen, vascular endothelial growth factor and CD31 (all P-values <0.001), markers of proliferation and angiogenesis. Staining for α-SMA, a marker for myofibroblast, desmin, smooth muscle myosin heavy chain and oxytocin receptor was significantly increased in adenomyotic lesions versus control, concomitant with increased staining of collagen I and lysyl oxidase (all P-values <0.001). Histochemistry analysis indicates that the extent of fibrosis is high in adenomyotic lesions (P < 0.001), and the extent appeared to correlate negatively with the microvessel density (P < 0.05). PR-B staining was significantly decreased in adenomyotic lesion as compared with control endometrium (P < 0.001). Platelets and HGF were co-localized mostly in the stromal component of adenomyotic lesions, near the glandular epithelium. LIMITATIONS, REASONS FOR CAUTION: The results are limited by the cross-sectional nature of the study and the use of histochemistry and immunohistochemistry analyses only, but nonetheless is a validation of our previous finding in mouse experiments. WIDER IMPLICATIONS OF THE FINDINGS: The data presented are consistent with the notion that platelet-induced activation of the TGF-ß/Smad signaling pathway may be a driving force in EMT, FMT and SMM in the development of adenomyosis, leading to fibrosis. This study provides the first piece of evidence that adenomyotic lesions are wounds that undergo repeated injury and healing, and, as such, platelets play critical roles in the development of adenomyosis by promoting proliferation, angiogenesis, increasing ECM deposits, and SMM, resulting in fibrosis. Platelets may also be involved in uterine hyperactivity and myometrial hyperinnervation. Our results provide one explanation as to why adenomyosis is a challenge for medical treatment, and shed new light onto the pathophysiology of adenomyosis. STUDY FUNDING/COMPETING INTERESTS: Support for data collection and analysis was provided by grants from the National Science Foundation of China. None of the authors has anything to disclose.

Cancer fitness genes: emerging therapeutic targets for metastasis.

Development of cancer therapeutics has traditionally focused on targeting driver oncogenes. Such an approach is limited by toxicity to normal tissues and treatment resistance. A class of 'cancer fitness genes' with crucial roles in metastasis have been identified. Elevated or altered activities of these genes do not directly cause cancer; instead, they relieve the stresses that tumor cells encounter and help them adapt to a changing microenvironment, thus facilitating tumor progression and metastasis. Importantly, as normal cells do not experience high levels of stress under physiological conditions, targeting cancer fitness genes is less likely to cause toxicity to noncancerous tissues. Here, we summarize the key features and function of cancer fitness genes and discuss their therapeutic potential.

Application of breast milk smears in umbilical care of full-term newborn.

With the continuous innovation of digital technology in my country at this stage and the design of medical imaging technology systems, the depth and breadth of the development of digital medical imaging technology have been greatly expanded. This paper focus on application of medical images in breast milk smearing of the umbilical nursing for full-term newborns. OBJECTIVE: To explore the effect of breast milk application in umbilical nursing of full-term newborns. METHODS: 596 full-term newborns were divided into three groups: Experimental Group, Control Group A and Control Group B, Experimental Group A treated with breast milk, control group a treated with 75% alcohol, and control group B treated with 37 ~ 42°C warm boiled water, the time of umbilical cord abscission, infection and other complications were compared among the three groups. The process was recorded by images. RESULTS: According to the images, compared with the Control Group A and B, the experimental group significantly shortened the time of umbilical cord shedding, the difference was statistically significant (p < 0.001). CONCLUSION: The application of breast milk in umbilical region of full-term neonates can reduce the time of umbilical cord abscission without increasing the incidence of Omphalitis.

Shorter Anogenital Distance in Women with Ovarian Endometriomas and Adenomyosis, but Not Uterine Leiomyomas.

We investigated whether anogenital distance (AGD) is associated with adenomyosis, endometriosis and uterine leiomyomas (UL, also called uterine fibroids). We recruited 81 women with UL, 105 with ovarian endometrioma (OE), 116 with adenomyosis, 28 with both adenomyosis and UL, and 100 control subjects with other acquired gynecological conditions but not endometriosis, adenomyosis, UL, or polycystic ovarian syndrome. Measurements from the anterior clitoral surface to the center of the anus (AGDAC), from the tip of the clitoris to the center of the anus (AGDACt), and from the posterior fourchette to the center of the anus (AGDAF) were made in all subjects. Multiple regression was performed to estimate the association between AGDs and presence of OE, adenomyosis, and UL while controlling for possible confounding factors. We found that, compared with controls, women with OE and adenomyosis, but not UL, had significantly shorter AGDAF, but not AGDAC. However, the amount of variance that could be explained by the disease status is rather moderate, suggesting that factors other than disease status, bodyweight and height were also responsible for AGD. Thus, prenatal exposure to reduced levels of androgen may increase the risk of developing endometriosis and adenomyosis. However, other factors may also contribute to the pathogenesis of endometriosis and adenomyosis.

Tumor Microenvironment Shapes Colorectal Cancer Progression, Metastasis, and Treatment Responses.

Colorectal cancer (CRC) is one of the most devastating diseases that accounts for numerous deaths worldwide. Tumor cell-autonomous pathways, such as the oncogenic signaling activation, significantly contribute to CRC progression and metastasis. Recent accumulating evidence suggests that the CRC microenvironment also profoundly promotes or represses this process. As the roles of the tumor microenvironment (TME) in CRC progression and metastasis is gradually uncovered, the importance of these non-cell-autonomous signaling pathways is appreciated. However, we are still at the beginning of this TME function exploring process. In this review, we summarize the current understanding of the TME in CRC progression and metastasis by focusing on the gut microbiota and host cellular and non-cellular components. We also briefly discuss TME-remodeling therapies in CRC.

Structure-Based Design, Optimization, and Evaluation of Potent Stabilized Peptide Inhibitors Disrupting MTDH and SND1 Interaction.

Blocking the interaction of MTDH/SND1 complex is an attractive strategy for cancer therapeutics. In this work, we designed and obtained a novel class of potent stabilized peptide inhibitors derived from MTDH sequence to disrupt MTDH/SND1 interaction. Through structure-based optimization and biological evaluation, stabilized peptides were obtained with tight binding affinity, improved cell penetration, and antitumor effects in the triple-negative breast cancer (TNBC) cells without nonspecific toxicity. To date, our study was the first report to demonstrate that stabilized peptides truncated from MTDH could serve as promising candidates to disrupt the MTDH/SND1 interaction for potential breast cancer treatment.

Pharmacological disruption of the MTDH-SND1 complex enhances tumor antigen presentation and synergizes with anti-PD-1 therapy in metastatic breast cancer.

Despite increased overall survival rates, curative options for metastatic breast cancer remain limited. We have previously shown that metadherin (MTDH) is frequently overexpressed in poor prognosis breast cancer, where it promotes metastasis and therapy resistance through its interaction with staphylococcal nuclease domain-containing 1 (SND1). Through genetic and pharmacological targeting of the MTDH-SND1 interaction, we reveal a key role for this complex in suppressing antitumor T cell responses in breast cancer. The MTDH-SND1 complex reduces tumor antigen presentation and inhibits T cell infiltration and activation by binding to and destabilizing Tap1/2 messenger RNAs, which encode key components of the antigen-presentation machinery. Following small-molecule compound C26-A6 treatment to disrupt the MTDH-SND1 complex, we showed enhanced immune surveillance and sensitivity to anti-programmed cell death protein 1 therapy in preclinical models of metastatic breast cancer, in support of this combination therapy as a viable approach to increase immune-checkpoint blockade therapy responses in metastatic breast cancer.

Small-molecule inhibitors that disrupt the MTDH-SND1 complex suppress breast cancer progression and metastasis.

Metastatic breast cancer is a leading health burden worldwide. Previous studies have shown that metadherin (MTDH) promotes breast cancer initiation, metastasis and therapy resistance; however, the therapeutic potential of targeting MTDH remains largely unexplored. Here, we used genetically modified mice and demonstrate that genetic ablation of Mtdh inhibits breast cancer development through disrupting the interaction with staphylococcal nuclease domain-containing 1 (SND1), which is required to sustain breast cancer progression in established tumors. We performed a small-molecule compound screening to identify a class of specific inhibitors that disrupts the protein-protein interaction (PPI) between MTDH and SND1 and show that our lead candidate compounds C26-A2 and C26-A6 suppressed tumor growth and metastasis and enhanced chemotherapy sensitivity in preclinical models of triple-negative breast cancer (TNBC). Our results demonstrate a significant therapeutic potential in targeting the MTDH-SND1 complex and identify a new class of therapeutic agents for metastatic breast cancer.

LCOR mediates interferon-independent tumor immunogenicity and responsiveness to immune-checkpoint blockade in triple-negative breast cancer.

Ligand-dependent corepressor (LCOR) mediates normal and malignant breast stem cell differentiation. Cancer stem cells (CSCs) generate phenotypic heterogeneity and drive therapy resistance, yet their role in immunotherapy is poorly understood. Here we show that immune-checkpoint blockade (ICB) therapy selects for LCORlow CSCs with reduced antigen processing/presentation machinery (APM) driving immune escape and ICB resistance in triple-negative breast cancer (TNBC). We unveil an unexpected function of LCOR as a master transcriptional activator of APM genes binding to IFN-stimulated response elements (ISREs) in an IFN signaling-independent manner. Through genetic modification of LCOR expression, we demonstrate its central role in modulation of tumor immunogenicity and ICB responsiveness. In TNBC, LCOR associates with ICB clinical response. Importantly, extracellular vesicle (EV) Lcor-messenger RNA therapy in combination with anti-PD-L1 overcame resistance and eradicated breast cancer metastasis in preclinical models. Collectively, these data support LCOR as a promising target for enhancement of ICB efficacy in TNBC, by boosting of tumor APM independently of IFN.

Development and external validation of a model for predicting adverse outcomes in women with preeclampsia: A retrospective study from two trans-regional centers in China.

OBJECTIVES: Preeclampsia is a common complication of pregnancy that causes health problems for both the mother and her fetus. This study aimed to develop and externally validate a model to predict adverse outcomes in preeclampsia in a trans-regional two-center retrospective cohort of Chinese women. STUDY DESIGN: To generate a model for the risk of women with adverse outcomes, we incorporated candidate variables in the development set in univariate, least absolute shrinkage and selection operator analysis and multivariable logistic regression. The performance of the model was evaluated for the receiver operating characteristic (ROC) curve, calibration and decision curve analysis. Further, we externally validated the model in an independent dataset. MAIN OUTCOME MEASURES: Composite adverse outcomes within 48 h of admission. RESULTS: There were 1 783 and 116 preeclampsia women in the development and validation set, respectively. The model included 10 predictors: gestational age at admission, irregular prenatal care, number of symptoms, mean arterial pressure, hematocrit, platelet count, fibrinogen, albumin, total bilirubin, and serum urea. The area under the ROC curve of the model was 0.867 in the development set and 0.841 in the external validation set. The calibration plots for the probability of adverse outcomes demonstrated a good correlation. Decision curve analysis further showed that our model had clinical application value. The nomogram and a software-based calculator (https://sdfyyfck.shinyapps.io/preeclampsia/) were constructed for convenient clinical use. CONCLUSIONS: Such a model could be used as a useful tool for the assessment of hypertensive-related complications in Chinese preeclampsia patients.

Therapeutic Targeting of Metadherin Suppresses Colorectal and Lung Cancer Progression and Metastasis.

Colorectal and lung cancers account for one-third of all cancer-related deaths worldwide. Previous studies suggested that metadherin (MTDH) is involved in the development of colorectal and lung cancers. However, how MTDH regulates the pathogenesis of these cancers remains largely unknown. Using genetically modified mouse models of spontaneous colorectal and lung cancers, we found that MTDH promotes cancer progression by facilitating Wnt activation and by inducing cytotoxic T-cell exhaustion, respectively. Moreover, we developed locked nucleic acid-modified (LNA) MTDH antisense oligonucleotides (ASO) that effectively and specifically suppress MTDH expression in vitro and in vivo. Treatments with MTDH ASOs in mouse models significantly attenuated progression and metastasis of colorectal, lung, and breast cancers. Our study opens a new avenue for developing therapies against colorectal and lung cancers by targeting MTDH using LNA-modified ASO. SIGNIFICANCE: This study provides new insights into the mechanism of MTDH in promoting colorectal and lung cancers, as well as genetic and pharmacologic evidence supporting the development of MTDH-targeting therapeutics.

Role Reversal: A Pro-metastatic Function of E-Cadherin.

Carcinoma cells often acquire mobility and invasiveness by undergoing epithelial-to-mesenchymal transition, and yet most metastatic lesions remain epithelial in nature. Recently, in Nature, Padmanaban et al. (2019) demonstrated that the quintessential epithelial marker E-cadherin promotes metastasis of invasive ductal breast carcinoma by enhancing the survival of tumor cells.

The Possible Role of Eukaryotic Translation Initiation Factor 3 Subunit e (eIF3e) in the Epithelial-Mesenchymal Transition in Adenomyosis.

Epithelial-mesenchymal transition (EMT) has been reported to be involved in adenomyosis by promoting cell invasion and fibrogenesis. But few studies have identified critical factors that regulate EMT process during adenomyosis. The eukaryotic translation initiation factor 3 subunit e (eIF3e) protein is a component of the multisubunit eIF3 complex essential for cap-dependent translation initiation. The aim of this study was to investigate whether eIF3e is involved in EMT in adenomyosis. Ectopic endometrial tissue samples were collected from 40 premenopausal women with ultrasonographically diagnosed and histologically confirmed adenomyosis. As controls, endometrial samples were obtained from 40 cycling premenopausal women patients who underwent surgery for benign gynecologic disorders or cervical intraepithelial neoplasia but without endometriosis, adenomyosis, nor uterine fibroids. All tissue samples were subjected to immunohistochemistry analysis of eIF3e, transforming growth factor-ß1 (TGF-ß1), E-cadherin, vimentin, Snail, and proliferating cell nuclear antigen (PCNA). The epithelial component of ectopic endometrium showed significantly reduced immunoreactivity against eIF3e and E-cadherin but elevated immunoreactivity against TGF-ß1, Snail, vimentin, and PCNA as compared with that of control endometrium (all P values <.05), and the difference was not affected by age, parity, or menstrual phase. The eIF3e staining levels correlated negatively with those of TGF-ß1, vimentin, Snail, and PCNA (both P values <.05). These data suggest that decreased eIF3e expression may pave way for EMT in the development of adenomyosis through activating the TGF-ß1 signaling pathway. Our study provided novel insights into the development and treatments of adenomyosis.

Tinagl1 Suppresses Triple-Negative Breast Cancer Progression and Metastasis by Simultaneously Inhibiting Integrin/FAK and EGFR Signaling.

Triple-negative breast cancer (TNBC) patients have the worst prognosis and distant metastasis-free survival among all major subtypes of breast cancer. The poor clinical outlook is further exacerbated by a lack of effective targeted therapies for TNBC. Here we show that ectopic expression and therapeutic delivery of the secreted protein Tubulointerstitial nephritis antigen-like 1 (Tinagl1) suppresses TNBC progression and metastasis through direct binding to integrin α5ß1, αvß1, and epidermal growth factor receptor (EGFR), and subsequent simultaneous inhibition of focal adhesion kinase (FAK) and EGFR signaling pathways. Moreover, Tinagl1 protein level is associated with good prognosis and reversely correlates with FAK and EGFR activation status in TNBC. Our results suggest Tinagl1 as a candidate therapeutic agent for TNBC by dual inhibition of integrin/FAK and EGFR signaling pathways.

pSTAT3+ Reactive Astrocytes Promote Brain Metastasis.

The tumor microenvironment contains heterogeneous populations of stromal cells with important roles in cancer progression and metastasis. In a recent study published in Nature Medicine, pSTAT3+ reactive astrocytes were found to promote brain metastasis by altering the tumor microenvironment, and represent a promising target for the treatment of brain metastasis.

Complex interplay between tumor microenvironment and cancer therapy.

Tumor microenvironment (TME) is comprised of cellular and non-cellular components that exist within and around the tumor mass. The TME is highly dynamic and its importance in different stages of cancer progression has been well recognized. A growing body of evidence suggests that TME also plays pivotal roles in cancer treatment responses. TME is significantly remodeled upon cancer therapies, and such change either enhances the responses or induces drug resistance. Given the importance of TME in tumor progression and therapy resistance, strategies that remodel TME to improve therapeutic responses are under developing. In this review, we provide an overview of the essential components in TME and the remodeling of TME in response to anti-cancer treatments. We also summarize the strategies that aim to enhance therapeutic efficacy by modulating TME.