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Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.

ABSTRACT: The vasculature serves as the main conduit for breast tumor metastases and is a target of therapeutics in many tumor types. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity across the intrinsic subtypes of human breast tumors. Analysis of gene expression signatures from more than 3,000 human breast tumors found that genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hypoxia-signature were the most highly expressed in claudin-low and basal-like tumors. The majority of the vascular gene signatures added metastasis-predictive information to immunohistochemistry-defined microvessel density scores and genomically defined-intrinsic subtype classification. Interestingly, pure claudin-low cell lines, and subsets of claudin-low-like cells within established basal-like cancer cell lines, exhibited endothelial/tube-like morphology when cultured on Matrigel. In vivo xenografts found that claudin-low tumors, but not luminal tumors, extensively perfused injected contrast agent through paracellular spaces and non-vascular tumor-lined channels. Taken together, the endothelial-like characteristics of the cancer cells, combined with both the amount and the physiologic state of the vasculature contribute to breast cancer metastatic progression. We hypothesize that the genetic signatures we have identified highlight patients that should respond most favorably to anti-vascular agents.

SUBMITTER: Harrell JC

PROVIDER: S-EPMC3892109 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.

Harrell J Chuck JC Pfefferle Adam D AD Zalles Nicole N Prat Aleix A Fan Cheng C Khramtsov Andrey A Olopade Olufunmilayo I OI Troester Melissa A MA Dudley Andrew C AC Perou Charles M CM

Clinical & experimental metastasis 20130822 1

The vasculature serves as the main conduit for breast tumor metastases and is a target of therapeutics in many tumor types. In this study, we aimed to determine if tumor-associated vascular properties could help to explain the differences observed in metastagenicity across the intrinsic subtypes of human breast tumors. Analysis of gene expression signatures from more than 3,000 human breast tumors found that genomic programs that measured vascular quantity, vascular proliferation, and a VEGF/Hyp ...[more]

PMID: 23975155

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Project description:BackgroundRecent studies show that exosomes are involved in intercellular communication and that abundant circular RNAs (circRNAs) are present within exosomes. However, whether these exosomal circRNAs contribute to tumor invasion and metastasis remains unclear, as do their associated mechanisms.MethodsQuantitative reverse transcription-polymerase chain reaction (qRT-PCR) was used to measure the expression levels of circ-IARS in 85 pancreatic ductal adenocarcinoma (PDAC) tissues, plasma exosomes, and Hs 766 T, Hs 766 T-L2 and human microvascular vein endothelial (HUVECs) cells. RhoA, ZO-1 and RhoA-GTP levels were detected by qRT-PCR and western blotting (WB); RhoA activity analysis was also performed. Transwell assays were performed to examine changes in endothelial monolayer permeability, and immunofluorescence and WB were employed to evaluate F-actin expression and focal adhesion. Finally, an animal experiment was performed to detect the contribution of circ-IARS to cancer metastasis.Resultscirc-IARS expression was up-regulated in pancreatic cancer tissues and in plasma exosomes of patients with metastatic disease. Circ-IARS was found to enter HUVECs through exosomes and promote tumor invasion and metastasis. Circ-IARS expression was positively correlated with liver metastasis, vascular invasion, and tumor-node-metastasis (TNM) stage and negatively correlated with postoperative survival time. Overexpression of circ-IARS significantly down-regulated miR-122 and ZO-1 levels, up-regulated RhoA and RhoA-GTP levels, increased F-actin expression and focal adhesion, enhanced endothelial monolayer permeability, and promoted tumor invasion and metastasis.Conclusionscirc-IRAS accesses HUVECs via exosomes derived from pancreatic cancer cells followed by increased endothelial monolayer permeability. Furthermore, this process promotes tumor invasion and metastasis. The results of this study suggest that the presence of circRNAs in exosomes may be important indicator for early diagnosis and prognostic prediction in PDAC.

Project description: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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Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.

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Endothelial-like properties of claudin-low breast cancer cells promote tumor vascular permeability and metastasis.

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