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- Yang, Q., et al.
(author)
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Morphological appearance, content of extracellular matrix and vascular density of lung metastases predicts permissiveness to infiltration by adoptively transferred natural killer and T cells.
- 2006
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In: Cancer immunology, immunotherapy : CII. - : Springer Science and Business Media LLC. - 0340-7004 .- 1432-0851. ; 55:6, s. 699-707
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Journal article (peer-reviewed)abstract
- We have recently shown that adoptively transferred, IL-2-activated natural killer (A-NK) cells are able to eliminate well-established B16-F10.P1 melanoma lung metastases. However, some B16-F10.P1 lung metastases were resistant to infiltration by the A-NK cells and also resistant to the A-NK cell treatment. The infiltration-resistant (I-R) B16-F10.P1 metastases had a unique "compact" morphology compared to the "loose" morphology of the infiltration-permissive (I-P) metastases. Here, we show that I-P loose tumors and I-R compact tumors are also found in lung metastases of mouse Lewis lung carcinoma (3LL), MCA-102 sarcoma, and MC38 colon carcinoma as well as rat MADB106 mammary carcinoma origin. Furthermore, the infiltration resistance of the compact tumors is not restricted to A-NK cells, since PHA and IL-2 stimulated CD8+ T-cells (T-LAK cells) also infiltrated the compact tumors poorly. Analyses of tumors for extracellular matrix (ECM) components and PECAM-1(+) vasculature, revealed that the I-R lesions are hypovascularized and contain very little laminin, collagen and fibronectin. In contrast, the I-P loose tumors are well-vascularized and they contain high amounts of ECM components. Interestingly, the distribution pattern of ECM components in the I-P loose tumors is almost identical to that of the normal lung tissue, indicating that these tumors develop around the alveolar walls which provide the loose tumors with both a supporting tissue and a rich blood supply. In conclusion, tumor infiltration by activated NK and T cells correlates with the presence of ECM components and PECAM-1(+) vasculature in the malignant tissue. Thus, analysis of the distribution of ECM and vasculature in tumor biopsies may help select patients most likely to benefit from cellular adoptive immunotherapy.
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- Albertsson, Per, 1964, et al.
(author)
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Differential locomotion of long- and short-term IL-2-activated murine natural killer cells in a model matrix environment.
- 2007
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In: Scandinavian journal of immunology. - : Wiley. - 0300-9475 .- 1365-3083. ; 66:4, s. 402-9
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Journal article (peer-reviewed)abstract
- Tumour infiltration by activated natural killer (A-NK) cells is a pre-requisite for tumour eradication by adoptive NK cell transfer. Extravasated A-NK cells do not always succeed in reaching the crucial target cell conjugation. Therefore, we wished to study A-NK cell locomotion and interactions with melanoma cells in a matrix environment (Matrigel) by electron, confocal and fluorescence microscopy. Two distinct patterns of A-NK cell-mediated matrix disintegration were revealed during incubation of tumour cells and A-NK cells in Matrigel: (1) A-NK cells pre-cultured for 5 days altered the homogeneous texture of the Matrigel, an initial microporous appearance became a loose filamentous meshwork by 24 h. Matrix degrading protease inhibitors could not fully prevent this, but could delay the process; and (2) A-NK cells pre-cultured for 6 days or more, instead formed large excavations in the Matrigel leaving the remaining matrix less affected compared to the effects by the younger A-NK cells. By histochemical staining with Cupromeronic Blue, the excavations were shown to contain proteoglycan material. Protease inhibitors had no discernable effect on the development of the excavations. The conspicuous capacity of A-NK cells to disintegrate extracellular matrix and the formation of large excavations seems only partially to depend on matrix-degrading proteases. Formation of extracellular proteoglycan material is suggested to facilitate A-NK cell locomotion within a matrix environment.
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- Edsparr, Karin, 1979, et al.
(author)
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Human NK cell lines migrate differentially in vitro related to matrix interaction and MMP expression.
- 2009
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In: Immunology and cell biology. - : Wiley. - 1440-1711 .- 0818-9641. ; 87:6, s. 489-95
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Journal article (peer-reviewed)abstract
- Matrix metalloproteinases (MMPs) are thought to be of importance for the migratory ability of natural killer (NK) cells. Their expression and production may influence the amount of tumour-infiltrating NK cells and thereby any therapeutic capability. In this study, we sought to investigate the importance of MMPs for human NK cells' ability to degrade and migrate through the extracellular matrix (ECM). The two human NK cell lines, NK-92 and YT, migratory ability, MMP expression and production as well as their morphological appearance when cultured in the ECM equivalent Matrigel were analysed and compared. The quantitatively more migratory NK-92 cells were found to express invadopodia/podosomes at a significantly higher degree when cultured in Matrigel and gave rise to a general disintegration of the Matrigel. The NK-92 cells had a higher mRNA expression of MMP-2, -9, -13, MT1-, MT3- and MT6-MMP and a significantly higher production of MMP-9 compared to YT cells. These differences could explain the substantial functional difference observed between the two cell lines with respect to migratory capacity. In addition, the number of Matrigel invading NK-92 cells decreased significantly in the presence of the MMP inhibitor GM6001, demonstrating that MMPs have a critical function in their migration.
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