Organotypic breast tumor model elucidates dynamic remodeling of tumor microenvironment

Singh, Sunil; Ray, Lucille A.; Thakuri, Pradip Shahi; Tran, Sydnie; Konopka, Michael; Luker, Gary D.; Tavana, Hossein

doi:10.1016/j.biomaterials.2020.119853

Cited by 26 publications

(25 citation statements)

References 60 publications

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“…Soluble ligands secreted by cancer cells bind to their cognate cell surface receptors present on stromal cells, or vice-versa, and activate specific signaling pathways. Cytokines are small protein (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20) involved in activating cell signaling by binding to specific cell surface receptor and regulate immunity, inflammation and hematopoiesis. Chemokines are smaller (8-14 kDa) cytokines that are predominantly involved in cell chemotaxis and trafficking.…”

Section: Different Mechanisms Of Tumor-stroma Communicationmentioning

confidence: 99%

“…Tumors are known to educate these inflammatory cells to support tumor growth and metastases (16). The major type of inflammatory immune cells in the TME is tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) (17)(18)(19)(20). Classically activated macrophages are the first line of immune defense and are known to clear pathogens from site of infection.…”

Section: Innate Immune Cellsmentioning

confidence: 99%

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The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

et al. 2020

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The intricate interplay between malignant cells and host cellular and non-cellular components play crucial role in different stages of tumor development, progression, and metastases. Tumor and stromal cells communicate to each other through receptors such as integrins and secretion of signaling molecules like growth factors, cytokines, chemokines and inflammatory mediators. Chemokines mediated signaling pathways have emerged as major mechanisms underlying multifaceted roles played by host cells during tumor progression. In response to tumor stimuli, host cells-derived chemokines further activates signaling cascades that support the ability of tumor cells to invade surrounding basement membrane and extra-cellular matrix. The host-derived chemokines act on endothelial cells to increase their permeability and facilitate tumor cells intravasation and extravasation. The tumor cells-host neutrophils interaction within the vasculature initiates chemokines driven recruitment of inflammatory cells that protects circulatory tumor cells from immune attack. Chemokines secreted by tumor cells and stromal immune and non-immune cells within the tumor microenvironment enter the circulation and are responsible for formation of a “pre-metastatic niche” like a “soil” in distant organs whereby circulating tumor cells “seed’ and colonize, leading to formation of metastatic foci. Given the importance of host derived chemokines in cancer progression and metastases several drugs like Mogamulizumab, Plerixafor, Repertaxin among others are part of ongoing clinical trial which target chemokines and their receptors against cancer pathogenesis. In this review, we focus on recent advances in understanding the complexity of chemokines network in tumor microenvironment, with an emphasis on chemokines secreted from host cells. We especially summarize the role of host-derived chemokines in different stages of metastases, including invasion, dissemination, migration into the vasculature, and seeding into the pre-metastatic niche. We finally provide a brief description of prospective drugs that target chemokines in different clinical trials against cancer.

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Section: Different Mechanisms Of Tumor-stroma Communicationmentioning

confidence: 99%

Section: Innate Immune Cellsmentioning

confidence: 99%

The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

et al. 2020

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“…CAFs-derived CXCL12 plays specific roles in TNBC. It enhances invasiveness of TNBC cells via ERK1/2 activation [ 97 ]. Furthermore, CXCL12 boosts TNBC cells migration via cytoskeletal rearrangements [ 98 ].…”

Section: The Cxcl12/cxcr4 Signaling Promotes Fibroblasts Transformmentioning

confidence: 99%

“…Furthermore, CXCL12 boosts TNBC cells migration via cytoskeletal rearrangements [ 98 ]. These effects can be blocked by a specific CXCR4 inhibitor, suggesting that disrupting the interactions with tumor microenvironment might be a promising therapeutic strategy for TNBC that lacks a targeted treatment [ 97 ].…”

Section: The Cxcl12/cxcr4 Signaling Promotes Fibroblasts Transformmentioning

confidence: 99%

The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis

Zielińska

Katanaev

2020

Cancers

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The CXCL12/CXCR4 signaling pathway has emerged in the recent years as a key player in breast cancer tumorigenesis. This pathway controls many aspects of breast cancer development including cancer cell proliferation, motility and metastasis to all target organs. Moreover, the CXCL12/CXCR4 cascade affects both immune and stromal cells, creating tumor-supporting microenvironment. In this review, we examine state-of-the-art knowledge about detrimental roles of the CXCL12/CXCR4 signaling, discuss its therapeutic potential and suggest further research directions beneficial both for basic research and personalized medicine in breast cancer.

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“…The durable or pathological complete response (pCR) is low in TNBC patients [ 2 , 3 , 4 , 5 ]. There is mounting evidence to suggest that the CXCL12-CXCR4 axis plays an important role in triple-negative breast cancer (TNBC) progression and metastasis [ 6 , 7 , 8 , 9 , 10 , 11 ]. Previously, we reported that the N-terminal LIM domain of LIM and SH3 protein 1 (LASP1) directly binds to CXCR4 through its C-terminal tail [ 12 , 13 ].…”

Section: Introductionmentioning

confidence: 99%

Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

Subramaniyan

Sridharan

Howard

et al. 2020

Cancers

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The CXCL12-CXCR4 axis plays a vital role in many steps of breast cancer metastasis, but the molecular mechanisms have not been fully elucidated. We previously reported that activation of CXCR4 by CXCL12 promotes the nuclear localization of LASP1 (LIM and SH3 protein 1). The nuclear LASP1 then interacts with Snail1 in triple-negative breast cancer (TNBC) cell lines. In this study, we report that the nuclear accumulation and retention of Snail1 was dependent on an increase in nuclear LASP1 levels driven by active CXCR4. The CXCR4-LASP1 axis may directly regulate the stabilization of nuclear Snail1, by upregulating nuclear levels of pS473-Akt, pS9-GSK-3β, A20, and LSD1. Furthermore, the activation of CXCR4 induced association of LASP1 with Snail1, A20, GSK-3β, and LSD1 endogenously. Thus, nuclear LASP1 may also regulate protein-protein interactions that facilitate the stability of Snail1. Genetic ablation of LASP1 resulted in the mislocalization of nuclear Snail1, loss of the ability of TNBC cells to invade Matrigel and a dysregulated expression of both epithelial and mesenchymal markers, including an increased expression of ALDH1A1, a marker for epithelial breast cancer stem-like cells. Our findings reveal a novel role for the CXCR4-LASP1 axis in facilitating the stability of nuclear localized Snail1.

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Organotypic breast tumor model elucidates dynamic remodeling of tumor microenvironment

Cited by 26 publications

References 60 publications

The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

The Roles of Stroma-Derived Chemokine in Different Stages of Cancer Metastases

The Signaling Duo CXCL12 and CXCR4: Chemokine Fuel for Breast Cancer Tumorigenesis

Role of the CXCR4-LASP1 Axis in the Stabilization of Snail1 in Triple-Negative Breast Cancer

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