Axis In Tumor Microenvironment Research Articles

Abstract 203: Promotion of metastasis of ERBB2-positive breast cancer by mesenchymal stem cells via exosomes-mediated activation of ERBB2/ERBB3→PI3K/Akt singaling pathway

Abstract Elevated expression of ERBB3 receptor correlates with increased distant metastasis of breast cancers with amplification and/or overexpression of ERBB2 (HER2/neu), which the underlying molecular mechanism remains unclear. In recent years, cumulative studies have demonstrated that mesenchymal stem cells (MSCs), one of the important cellular components in tumor microenvironment, play important roles in multiple hallmarks of cancer including invasion and metastasis. However, its role in metastasis of ERBB2-positive breast cancer as well as the precise mechanisms are largely unrevealed. In our current study, we found that co-culture with MSCs or treatment with exosomes derived from MSCs can significantly promote the epithelial-mesenchymal transition (EMT), migration and invasion of ERBB2-positive breast cancer cells. MSCs exhibited significantly higher expression of NRG-1, a known ligand of ERBB3, as compared with ERBB2-positive breast cancer cells. The presence of NRG-1 in exosomes derived from MSCs was also evidenced. Mechanistically, co-culture with MSCs or treatment with exosomes derived from MSCs induced upregulation of ZEB1 and Slug via activation of downstream PI3K/Akt singaling to promote EMT of ERBB2-positive breast cancer cells. In addition, the expression of MMP2 was also upregulated by treatment with MSCs-derived exosomes, which enhanced the migration and invasion of ERBB2-positive breast cancer cells simultaneously. Interestingly, our study further demonstrated that treatment with MSCs-derived exosomes could significantly downregulate the expression of PTEN, the key negative regulator of PI3K/Akt singaling, via transferring three PTEN-targeting miRNAs (miR-21-5p, miR-23a-3p, and miR-148a-3p). Taken together, we presented here that MSCs may, on the one hand, directly activate the ERBB2/ERBB3→PI3K/Akt signaling pathway in ERBB2-positive breast cancer cells through the expression and secretion of NRG-1 via exosomes. Meanwhile, miR-21-5p, miR-23a-3p, and miR-148a-3p targeted delivery by exosomes specifically downregulated the expression of PETN, thus reliefs the negative regulation of PI3K/Akt signaling in ERBB2-positive breast cancer cells. These effects of MSCs act in concert to promote the metastasis of ERBB2-positive breast cancer. Our study lays a theoretical foundation and preliminary experimental basis for the development of novel combined therapies for patient with ERBB2-positive breast cancer through co-targeting MSC-derived NRG-1 and miR-21-5p, miR23a-3p, miR148a-3p/PTEN axis in tumor microenvironment in the future. Citation Format: Yating Wu, Li Chen, Yue Cao, Qinfeng Huang, Huimin Niu, Xiaofeng Lai, Meng Zhao, Huihui Yan, Hui Lyu, Bolin Liu, Shenghang Zhang, Shuiliang Wang. Promotion of metastasis of ERBB2-positive breast cancer by mesenchymal stem cells via exosomes-mediated activation of ERBB2/ERBB3→PI3K/Akt singaling pathway [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 203.

Candida albicans-myeloid cells-T lymphocytes axis in the tumor microenvironment of oral tumor-bearing mice

Candida albicans (C. albicans) is associated with the development of oral cancer. Here, we report the altered tumor microenvironment in oral tumor-bearing mice caused by C. albicans infection. Single-cell RNA sequencing showed that C. albicans infection influenced the tumor microenvironment significantly. Specifically, C. albicans infection reduced the CD8+ T cells but increased the IL-17A+ CD4+ T cells and IL-17A+ γδ T cells in oral tumor. The neutralization of IL-17A or TCR γ/δ alleviated the tumor progression caused by C. albicans infection. Additionally, C. albicans infection promoted the infiltration of myeloid-derived suppressor cells (MDSCs) into tumor, especially polymorphonuclear (PMN)-MDSCs, which infiltration was reduced after the neutralization of CCL2. Thus, our findings reveal the myeloid cells-T lymphocytes axis in oral tumor microenvironment with C. albicans infection, which helps to understand the mechanisms for C. albicans promoting oral cancer from the perspective of immune microenvironment.

CTGF/CCN2 promotes the proliferation of human osteosarcoma cells via cross-talking with the stromal CXCL12/CXCR4-AKT-αvβ3 signaling axis in tumor microenvironment

CTGF/CCN2 promotes the proliferation of human osteosarcoma cells via cross-talking with the stromal CXCL12/CXCR4-AKT-αvβ3 signaling axis in tumor microenvironment

CXCL5/CXCR2 axis in tumor microenvironment as potential diagnostic biomarker and therapeutic target.

The components of the tumor microenvironment (TME) in solid tumors, especially chemokines, are currently attracting much attention from scientists. C‐X‐C motif chemokine ligand 5 (CXCL5) is one of the important chemokines in TME. Overexpression of CXCL5 is closely related to the survival time, recurrence and metastasis of cancer patients. In TME, CXCL5 binds to its receptors, such as C‐X‐C motif chemokine receptor 2 (CXCR2), to participate in the recruitment of immune cells and promote angiogenesis, tumor growth, and metastasis. The CXCL5/CXCR2 axis can act as a bridge between tumor cells and host cells in TME. Blocking the transmission of CXCL5/CXCR2 signals can increase the sensitivity and effectiveness of immunotherapy and slow down tumor progression. CXCL5 and CXCR2 are also regarded as biomarkers for predicting prognosis and molecular targets for customizing the treatment. In this review, we summarized the current literature regarding the biological functions and clinical significance of CXCL5/CXCR2 axis in TME. The possibility to use CXCL5 and CXCR2 as potential prognostic biomarkers and therapeutic targets in cancer is also discussed

G-protein-coupled receptor 81 promotes a malignant phenotype in breast cancer through angiogenic factor secretion

G-protein-coupled receptor 81 (GPR81) functions as a receptor for lactate and plays an important role in the regulation of anti-lipolytic effects in adipocytes. However, to data, a role for GPR81 in the tumor microenvironment has not been clearly defined. Here, GPR81 expression in breast cancer patients and several breast cancer cell lines was significantly increased compared with normal mammary tissues and cells. GPR81 knockdown resulted in impaired breast cancer growth and led to apoptosis both in vitro and in vivo. Furthermore, the inhibition of GPR81 signaling suppressed angiogenesis through a phosphoinositide 3-OH kinase (PI3K)/Akt-cAMP response element binding protein (CREB) pathway, which led to decreased production of the pro-angiogenic mediator amphiregulin (AREG). Overall, these findings identify GPR81 as a tumor-promoting receptor in breast cancer progression and suggest a novel mechanism that regulates GPR81-dependent activation of the PI3K/Akt signaling axis in tumor microenvironment.

Abstract 1272: Apelin/Apj pathway for targeting ovarian tumor microenvironment

Abstract Introduction: Ovarian cancer generates unique tumor microenvironment (TME) that promotes and enhances tumor progression and metastasis. Current therapy option for modulating ovarian TME is antiangiogenic therapy but its clinical benefit is limited; thus, alternative drug targets are needed for therapeutic durability. Apelin and its cognate receptor APJ is known to have roles in glucose metabolism, cardiovascular functions, and angiogenesis. We found that apelin/APJ are highly overexpressed in human ovarian tumors, but their functional role is unclear. We also found a significant upregulation of apelin/APJ in tumors that progressed after antiangiogenic therapy in preclinical ovarian cancer models. Our objective is to determine the functional roles and mechanisms of apelin/APJ pathway on promoting ovarian tumor angiogenesis and progression. Methods: We examined autocrine and paracrine functions of apelin/APJ signaling on cell proliferation, migration, and tube formation using human ovarian cancer cells (SKOV3Apln and SKOV3Apj) and endothelial cells (HUVECApj). Phosphoproteome array was performed to evaluate the apelin/APJ downstream signaling. We characterized the effect of apelin or APJ overexpression on tumor development and response to VEGFR inhibitor in vivo. To confirm the clinical relevance of apelin/APJ in ovarian TME, we measured soluble apelin levels in patients’ ascites and APJ expressions in human ovarian tumors using an immunohistochemistry. Results: Apelin (10-100 ng/ml) induced mitogenic and chemoattractant effects on both cancer and endothelial cells. These effects were more prominent under hypoxic condition, reflecting the significance of apelin/APJ axis in TME. The aplein-mediated proliferative and migratory effects were inhibited by a pharmacological APJ inhibitor (ML-221) in a dose-dependent manner. High APJ expression resulted in enhanced pro-angiogenic activity in HUVEC. Overexpression of apelin/APJ also led to reduced response to antiangiogenic treatment in both HUVEC and cancer cells. Apelin signaling induces phosphorylation of AKT, STAT, CREB, PRAS 40, and AMPKα2 in SKOV3 cells. Our xenograft study indicates APJ-overexpressing tumors showed reduced response to sorafenib treatment compared to those control tumors. We found that APJ is mainly expressed in tumors and some extent in stromal component of human ovarian tumors. The median soluble apelin levels in ascites were 187 pg/ml (6.3 - 4,000 pg/ml). Conclusions: Our results suggest that apelin/APJ may play an important role in promoting angiogenesis and progression in ovarian cancer and serve as an attractive pathway targeting ovarian TME. Citation Format: Bharat Kumar Devapatla, Pharavee Jaiprasart, Samrita Dogra, Jihee Ha, Sukyung Woo. Apelin/Apj pathway for targeting ovarian tumor microenvironment. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1272.

Targeting the tumor-stromal-immune cell axis.

Targeting the tumor-stromal-immune cell axis.

HGF/c-MET Axis in Tumor Microenvironment and Metastasis Formation.

Tumor metastases are responsible for approximately 90% of all cancer-related deaths. Metastasis formation is a multistep process that requires acquisition by tumor cells of a malignant phenotype that allows them to escape from the primary tumor site and invade other organs. Each step of this mechanism involves a deep crosstalk between tumor cells and their microenvironment where the host cells play a key role in influencing metastatic behavior through the release of many secreted factors. Among these signaling molecules, Hepatocyte Growth Factor (HGF) is released by many cell types of the tumor microenvironment to target its receptor c-MET within the cells of the primary tumor. Many studies reveal that HGF/c-MET axis is implicated in various human cancers, and genetic and epigenetic gain of functions of this signaling contributes to cancer development through a variety of mechanisms. In this review, we describe the specific types of cells in the tumor microenvironment that release HGF in order to promote the metastatic outgrowth through the activation of extracellular matrix remodeling, inflammation, migration, angiogenesis, and invasion. We dissect the potential use of new molecules that interfere with the HGF/c-MET axis as therapeutic targets for future clinical trials in cancer disease.