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. 2011 Mar 1;108(9):3725-30.
doi: 10.1073/pnas.1100446108. Epub 2011 Feb 14.

Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation

Sachie Hiratsuka  1 , Shom Goel, Walid S Kamoun, Yoshiro Maru, Dai Fukumura, Dan G Duda, Rakesh K Jain
Affiliations

Endothelial focal adhesion kinase mediates cancer cell homing to discrete regions of the lungs via E-selectin up-regulation (VSports最新版本)

Sachie Hiratsuka et al. Proc Natl Acad Sci U S A. .

Abstract

Primary tumors secrete factors that alter the microenvironment of distant organs, rendering those organs as fertile soil for subsequent metastatic cancer cell colonization. Although the lungs are exposed to these factors ubiquitously, lung metastases usually develop as a series of discrete lesions VSports手机版. The underlining molecular mechanisms of the formation of these discrete lesions are not understood. Here we show that primary tumors induce formation of discrete foci of vascular hyperpermeability in premetastatic lungs. This is mediated by endothelial cell-focal adhesion kinase (FAK), which up-regulates E-selectin, leading to preferential homing of metastatic cancer cells to these foci. Suppression of endothelial-FAK or E-selectin activity attenuates the number of cancer cells homing to these foci. Thus, localized activation of endothelial FAK and E-selectin in the lung vasculature mediates the initial homing of metastatic cancer cells to specific foci in the lungs. .

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Conflict of interest statement

Conflict of interest statement: R V体育安卓版. K. J. received commercial research grants from Dyax, AstraZeneca, and MedImmune; consultant fees from AstraZeneca/MedImmune, Dyax, Astellas-Fibrogen, SynDevRx, Regeneron, Genzyme, Morphosys, and Noxxon Pharma; and a speaker honorarium from Genzyme. R. K. J. owns stock in SynDevRx. No reagents or funding from these companies was used in these studies. There is no significant financial or other competing interest in the work.

Figures

Fig. 1.
Fig. 1.
Formation of hyperpermeable foci by distant tumors. (A) Representative images of and quantification of EB leakage in the lungs of mice bearing s.c. primary E0771 or LLC tumors, measured 3 h after EB injection. *P < 0.05, **P < 0.01 vs. s.c. PBS injection, n = 4–6. (B) Representative images of EB leakage into lungs of healthy mice 3 h after stimulation with LTCM or NTCM. LTCM and ETCM significantly increased EB leakage; *P < 0.05 vs. NTCM, n = 6. (C) Total EB leakage in the liver, kidney, and brain of healthy mice after stimulation by tail vein injection of NTCM or ETCM (n = 6). (D) Total EB leakage in the lung and liver of healthy mice after stimulation by intracardiac injection of NTCM vs. LTCM. *P < 0.05, n = 4. Error bars are SEM.
Fig. 2.
Fig. 2.
Preferential homing of circulating cancer cells to regions of hyperpermeability in the lungs. (A) Schematic of a three-step, acute assay system to quantify metastatic cancer cell homing to different regions in stimulated lungs. (B) Representative images and quantification of i.v. injected metastatic cancer cells homed to areas of high vs. low EB leakage in the lungs of healthy mice stimulated by ETCM or LTCM measured 5 h after injection. n = 6, *P < 0.05. (C) Quantitation of microbead density (pixel/pixel) in microscopic fields surrounding metastatic cancer cells vs. paired microscopic fields with no tumor cells in the lungs of healthy mice stimulated by LTCM, NTCM, rVEGF, or PBS. *P < 0.05; y-axis scale is in multiples of 10−3; n = 16. Error bars are SEM.
Fig. 3.
Fig. 3.
Specific blockade of endothelial cell FAK activity reduces regional hyperpermeability, metastatic cancer cell homing, and the formation of macroscopic metastases. (A) Staining for pFAK (Y397) normalized by tissue area (pixel/pixel) in EB-high vs. EB-low leakage regions 3 h after stimulation by ETCM in wild-type mice, as measured by immunohistochemistry. *P < 0.05, n = 4. (B) Macroscopic distribution of EB leakage in the lungs of wild-type and tTA-FRNK (endothelial cell-specific) mice after stimulation with i.v. injection of ETCM. (C) Quantification of EB leakage in the lungs stimulated with i.v. injection of ETCM or LTCM (measured 3.5 h after EB injection). *P < 0.05, n = 6. (D) Metastatic cancer cell homing to the lungs of wild-type and tTA-FRNK mice after stimulation with i.v. injection of NTCM, ETCM, or LTCM. *P < 0.05, n = 6. (E) Metastatic cancer cell homing to the lungs of tumor-bearing wild-type and tTA-FRNK mice after stimulation with i.v. TCM, measured 48 h after i.v. injection of metastatic cancer cells. *P < 0.05, n = 5. (F) Number of macroscopic lung metastases in the lungs of WT mice and tTA-FRNK mice (either with tetracycline/sucrose drinking water or sucrose control) 3 wk after i.v. injection of LTCM and LLC cells. *P < 0.05, n = 4. Error bars are SEM.
Fig. 4.
Fig. 4.
E-selectin is up-regulated by endothelial FAK activation in hyperpermeable areas and mediates metastatic cancer cell homing in vivo. (A) E-selectin expression in areas of high vs. low EB leakage in wild-type mice stimulated with i.v. ETCM (as measured by immunohistochemistry). *P < 0.05, n = 4. (B) E-selectin expression in wild-type vs. tTA-FRNK mice stimulated with i.v. ETCM. *P < 0.05, n = 4. (C) In vivo assay of tumor cell homing to ETCM-stimulated lungs of wild-type and tTA-FRNK mice, with or without administration of an E-selectin blocking antibody. *P < 0.05, n = 3–4. (D) Number of metastatic cancer cells homing to areas of high vs. low EB leakage in the lungs of wild-type and E-selectin−/− mice 5 h after stimulation with i.v. ETCM. *P < 0.05, n = 4. (E) Metastatic cancer cell homing to the lungs of age- and sex-matched C57BL/6 (wild-type) and E-selectin−/− mice 24 h after stimulation with i.v. ETCM. *P < 0.05, n = 4. (F) Metastatic cancer cell homing to the lungs of tumor-bearing wild-type and E-selectin−/− mice measured 48 h after TCM and tumor cell injection. *P < 0.05, n = 4. Error bars are SEM.
Fig. 5.
Fig. 5.
Increased tumor cell adhesion to lung endothelial cells is mediated by E-selectin expression stimulated by FAK in vitro. (A) E-selectin expression on wild-type and tTA-FRNK primary lung endothelial cells after stimulation by PBS or rVEGF. *P < 0.05, n = 10. (B) Immunohistochemical detection of E-selectin expression in primary lung endothelial cells isolated from wild-type mice after 4 h of stimulation with 100 ng/mL rVEGF or PBS. (C) Representative images of rhodamine-labeled E0771 tumor cells (red) adherent to lung endothelial cells (blue), stained for E-selectin (green), in an in vitro tumor cell–endothelial cell adhesion assay. (D) In vitro assay of tumor cell adhesion to VEGF-stimulated primary lung endothelial cells in wild-type and tTA-FRNK mice. Data are shown as number of E0771 cells adhering to endothelial cells after incubation with or without anti–E-selectin blocking antibody. *P < 0.05, n = 3. Error bars are SEM.
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"VSports" References

    1. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;1:571–573. - PubMed
    1. Fidler IJ. The pathogenesis of cancer metastasis: The ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–458. - PubMed
    1. Gupta GP, et al. Mediators of vascular remodelling co-opted for sequential steps in lung metastasis. Nature. 2007;446:765–770. - PubMed
    1. Talmadge JE, Fidler IJ. AACR centennial series: The biology of cancer metastasis: Historical perspective. Cancer Res. 2010;70:5649–5669. - PMC - PubMed
    1. Hiratsuka S, et al. MMP9 induction by vascular endothelial growth factor receptor-1 is involved in lung-specific metastasis. Cancer Cell. 2002;2:289–300. - PubMed

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