scholarly journals Targeting AXL and RAGE to prevent geminin overexpression-induced triple-negative breast cancer metastasis

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniel Ryan ◽  
Jim Koziol ◽  
Wael M. ElShamy
Keyword(s):  
Tumor Cells ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Tumor Stroma ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Cancer Associated Fibroblasts ◽  
Patient Death ◽  
Functional Interaction ◽  
Α3β1 Integrin

AbstractDissemination of metastatic precursors from primaries is the primary reason for patient death. Dissemination encompasses tumor cells invasion of stroma, followed by intravasation through the endothelium barrier into the bloodstream. Here, we describe how geminin-overexpressing tumor cells acquire dissemination ability. Acetylated HMGB1 (Ac-HMGB1) secreted by geminin-overexpressing cells activates RAGE and CXCR4 expression on mesenchymal stem cells (MSCs) located in tumor stroma. Through secreting CXCL12, geminin-overexpressing cells recruit these CXCR4+-MSCs into the tumor. Within the tumor, MSCs differentiate into S100A4-secreting cancer-associated fibroblasts (CAFs). S100A4, in a reciprocal manner, activates geminin-overexpressing cells to secrete CCL2 that recruits M0-macrophages from the stroma into the tumor. Within the tumor, CCL2 polarizes M0-macrophages into Gas6-secreting M2-tumor-associated macrophages (M2-TAMs). In concert, geminin-overexpression, S100A4/RAGE and Gas6/AXL signaling promote the invasive and intravasation abilities in geminin-overexpressing cells through exacerbating their stemness and epithelial-to-mesenchymal phenotypes and enhancing expression and functional interaction of CD151 and α3β1-integrin in geminin-overexpressing cells. Tumors formed following injection of geminin-overexpressing cells admixed with MSCs/CAFs grew faster, metastasized earlier, especially to lungs, and were extremely sensitive to anti-c-Abl, anti-RAGE, and anti-AXL drugs. These data support an intrinsic ability in geminin-overexpressing tumor cells to promote their metastatic potential through recruitment and bi-directional interactions with MSCs/CAFs and M2-TAMs.

scholarly journals miR-200 deficiency promotes lung cancer metastasis by activating cancer-associated fibroblasts

2020 ◽  
Author(s):  
Bin Xue ◽  
Chen-Hua Chuang ◽  
Haydn M. Prosser ◽  
Cesar Seigi Fuziwara ◽  
Claudia Chan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Cancer Metastasis ◽  
Lung Cancer Mortality ◽  
Tumor Stroma ◽  
Metastatic Potential ◽  
Human Lung Cancer ◽  
Cancer Associated Fibroblasts

AbstractLung adenocarcinoma, the most prevalent lung cancer subtype, is characterized by its high propensity to metastasize. Despite the importance of metastasis in lung cancer mortality, its underlying cellular and molecular mechanisms remain largely elusive. Here, we identified miR-200 miRNAs as potent suppressors for lung adenocarcinoma metastasis. miR-200 expression is specifically repressed in mouse metastatic lung adenocarcinomas, and miR-200 decrease strongly correlates with poor patient survival. Consistently, deletion of mir-200c/141 in the KrasLSL-G12D/+; Trp53flox/flox lung adenocarcinoma mouse model significantly promoted metastasis, generating a desmoplastic tumor stroma highly reminiscent of metastatic human lung cancer. miR-200 deficiency in lung cancer cells promotes the proliferation and activation of adjacent cancer-associated fibroblasts (CAFs), which in turn elevates the metastatic potential of cancer cells. miR-200 regulates the functional interaction between cancer cells and CAFs, at least in part, by targeting Notch ligand Jagged1 and Jagged2 in cancer cells and inducing Notch activation in adjacent CAFs. Hence, the interaction between cancer cells and CAFs constitutes an essential mechanism to promote metastatic potential.

scholarly journals The Activity of KIF14, Mieap, and EZR in a New Type of the Invasive Component, Torpedo-Like Structures, Predetermines the Metastatic Potential of Breast Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1909
Author(s):  
Tatiana S. Gerashchenko ◽  
Sofia Y. Zolotaryova ◽  
Artem M. Kiselev ◽  
Liubov A. Tashireva ◽  
Nikita M. Novikov ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Ether Lipid ◽  
Metastatic Tumor ◽  
Metastatic Potential ◽  
Breast Cancer Metastasis ◽  
Breast Cancers ◽  
Invasive Component ◽  
Positive Expression

Intratumor morphological heterogeneity reflects patterns of invasive growth and is an indicator of the metastatic potential of breast cancer. In this study, we used this heterogeneity to identify molecules associated with breast cancer invasion and metastasis. The gene expression microarray data were used to identify genes differentially expressed between solid, trabecular, and other morphological arrangements of tumor cells. Immunohistochemistry was applied to evaluate the association of the selected proteins with metastasis. RNA-sequencing was performed to analyze the molecular makeup of metastatic tumor cells. High frequency of metastases and decreased metastasis-free survival were detected in patients either with positive expression of KIF14 or Mieap or negative expression of EZR at the tips of the torpedo-like structures in breast cancers. KIF14- and Mieap-positive and EZR-negative cells were mainly detected in the torpedo-like structures of the same breast tumors; however, their transcriptomic features differed. KIF14-positive cells showed a significant upregulation of genes involved in ether lipid metabolism. Mieap-positive cells were enriched in genes involved in mitophagy. EZR-negative cells displayed upregulated genes associated with phagocytosis and the chemokine-mediated signaling pathway. In conclusion, the positive expression of KIF14 and Mieap and negative expression of EZR at the tips of the torpedo-like structures are associated with breast cancer metastasis.

scholarly journals The Action of Discoidin Domain Receptor 2 in Basal Tumor Cells and Stromal Cancer-Associated Fibroblasts Is Critical for Breast Cancer Metastasis

Cell Reports ◽  
2016 ◽  
Vol 15 (11) ◽  
pp. 2510-2523 ◽  
Author(s):  
Callie A.S. Corsa ◽  
Audrey Brenot ◽  
Whitney R. Grither ◽  
Samantha Van Hove ◽  
Andrew J. Loza ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Cancer Associated Fibroblasts ◽  
Discoidin Domain Receptor ◽  
Discoidin Domain Receptor 2

scholarly journals Dangerous Liaisons: Circulating Tumor Cells (CTCs) and Cancer-Associated Fibroblasts (CAFs)

Cancers ◽  
2020 ◽  
Vol 12 (10) ◽  
pp. 2861
Author(s):  
Pablo Hurtado ◽  
Inés Martínez-Pena ◽  
Roberto Piñeiro
Keyword(s):  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Cancer Metastasis ◽  
Current Knowledge ◽  
Single Cells ◽  
Metastatic Potential ◽  
Cancer Associated Fibroblasts ◽  
Cytokines And Chemokines ◽  
Paracrine Secretion ◽  
Cellular Components

The crosstalk between cancer cells and the tumor microenvironment (TME) is a key determinant of cancer metastasis. Cancer-associated fibroblasts (CAFs), one of the main cellular components of TME, promote cancer cell invasion and dissemination through mechanisms including cell-cell interactions and the paracrine secretion of growth factors, cytokines and chemokines. During metastasis, circulating tumor cells (CTCs) are shed from the primary tumor to the bloodstream, where they can be detected as single cells or clusters. The current knowledge about the biology of CTC clusters positions them as key actors in metastasis formation. It also indicates that CTCs do not act alone and that they may be aided by stromal and immune cells, which seem to shape their metastatic potential. Among these cells, CAFs are found associated with CTCs in heterotypic CTC clusters, and their presence seems to increase their metastatic efficiency. In this review, we summarize the current knowledge on the role that CAFs play on metastasis and we discuss their implication on the biogenesis, metastasis-initiating capacity of CTC clusters, and clinical implications. Moreover, we speculate about possible therapeutic strategies aimed to limit the metastatic potential of CTC clusters involving the targeting of CAFs as well as their difficulties and limitations.

scholarly journals Entelon® (Vitis vinifera Seed Extract) Prevents Cancer Metastasis via the Downregulation of Interleukin-1 Alpha in Triple-Negative Breast Cancer Cells

Molecules ◽  
2021 ◽  
Vol 26 (12) ◽  
pp. 3644
Author(s):  
Daeun You ◽  
Yisun Jeong ◽  
Sun Young Yoon ◽  
Sung A Kim ◽  
Eunji Lo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Signaling Pathway ◽  
Lung Metastasis ◽  
Triple Negative Breast Cancer ◽  
Cancer Metastasis ◽  
Triple Negative ◽  
Interleukin 1 ◽  
Metastatic Potential ◽  
Cancer Cell Proliferation ◽  
Dependent Pathway

Interleukin-1 (IL1) is a proinflammatory cytokine and promotes cancer cell proliferation and invasiveness in a diversity of cancers, such as breast and colon cancer. Here, we focused on the pharmacological effect of Entelon® (ETL) on the tumorigenesis of triple-negative breast cancer (TNBC) cells by IL1-alpha (IL1A). IL1A enhanced the cell growth and invasiveness of TNBC cells. We observed that abnormal IL1A induction is related with the poor prognosis of TNBC patients. IL1A also increased a variety of chemokines such as CCL2 and IL8. Interestingly, IL1A expression was reduced by the ETL treatment. Here, we found that ETL significantly decreased the MEK/ERK signaling pathway in TNBC cells. IL1A expression was reduced by UO126. Lastly, we studied the effect of ETL on the metastatic potential of TNBC cells. Our results showed that ETL significantly reduced the lung metastasis of TNBC cells. Our results showed that IL1A expression was regulated by the MEK/ERK- and PI3K/AKT-dependent pathway. Taken together, ETL inhibited the MEK/ERK and PI3K/AKT signaling pathway and suppressing the lung metastasis of TNBC cells through downregulation of IL1A. Therefore, we propose the possibility of ETL as an effective adjuvant for treating TNBC.

scholarly journals Fibronectin-Expressing Mesenchymal Tumor Cells Promote Breast Cancer Metastasis

Cancers ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2553 ◽  
Author(s):  
Brian H. Jun ◽  
Tianqi Guo ◽  
Sarah Libring ◽  
Monica K. Chanda ◽  
Juan Sebastian Paez ◽  
...  
Keyword(s):  
Tumor Cells ◽  
Cell Tracking ◽  
Cancer Metastasis ◽  
Breast Cancer Metastasis ◽  
Mesenchymal Tumor ◽  
Minority Population ◽  
Metastatic Niche ◽  
Epithelial Tumor ◽  
Epithelial Tumor Cells ◽  
Cell Series

Tumor metastasis is connected to epithelial-mesenchymal heterogeneity (EMH) and the extracellular matrix (ECM) within the tumor microenvironment. Mesenchymal-like fibronectin (FN) expressing tumor cells enhance metastasis within tumors that have EMH. However, the secondary tumors are primarily composed of the FN null population. Interestingly, during tumor cell dissemination, the invasive front has more mesenchymal-like characteristics, although the outgrowths of metastatic colonies consist of a more epithelial-like population of cells. We hypothesize that soluble FN provided by mesenchymal-like tumor cells plays a role in supporting the survival of the more epithelial-like tumor cells within the metastatic niche in a paracrine manner. Furthermore, due to a lower rate of proliferation, the mesenchymal-like tumor cells become a minority population within the metastatic niche. In this study, we utilized a multi-parametric cell-tracking algorithm and immunoblotting to evaluate the effect of EMH on the growth and invasion of an isogenic cell series within a 3D collagen network using a microfluidic platform. Using the MCF10A progression series, we demonstrated that co-culture with FN-expressing MCF10CA1h cells significantly enhanced the survival of the more epithelial MCF10CA1a cells, with a two-fold increase in the population after 5 days in co-culture, whereas the population of the MCF10CA1a cells began to decrease after 2.5 days when cultured alone (p < 0.001). However, co-culture did not significantly alter the rate of proliferation for the more mesenchymal MCF10CA1h cells. Epithelial tumor cells not only showed prolonged survival, but migrated significantly longer distances (350 µm compared with 150 µm, respectively, p < 0.01) and with greater velocity magnitude (4.5 µm/h compared with 2.1 µm/h, respectively, p < 0.001) under co-culture conditions and in response to exogenously administered FN. Genetic depletion of FN from the MCF10CA1h cells resulted in a loss of survival and migration capacity of the epithelial and mesenchymal populations. These data suggest that mesenchymal tumor cells may function to support the survival and outgrowth of more epithelial tumor cells within the metastatic niche and that inhibition of FN production may provide a valuable target for treating metastatic disease.

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