Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2012 Jan;33(3):876-85.
doi: 10.1016/j.biomaterials.2011.10.002. Epub 2011 Oct 22.

The use of chemokine-releasing tissue engineering scaffolds in a model of inflammatory response-mediated melanoma cancer metastasis

Cheng-Yu Ko  1 , Lanxiao Wu, Ashwin M Nair, Yi-Ting Tsai, Victor K Lin, Liping Tang
Affiliations

The use of chemokine-releasing tissue engineering scaffolds in a model of inflammatory response-mediated melanoma cancer metastasis

Cheng-Yu Ko et al. Biomaterials. 2012 Jan.

Abstract

Inflammatory responses and associated products have been implicated in cancer metastasis. However, the relationship between these two processes is uncertain due to the lack of a suitable model. Taking advantage of localized and controllable inflammatory responses induced by biomaterial implantation and the capability of tissue scaffolds to release a wide variety of chemokines, we report a novel system for studying the molecular mechanisms of inflammation-mediated cancer metastasis. The animal model is comprised of an initial subcutaneous implantation of biomaterial microspheres which prompt localized inflammatory responses, followed by the transplantation of metastatic cancer cells into the peritoneal cavity or blood circulation. Histological results demonstrated that substantial numbers of B16F10 cells were recruited to the site nearby biomaterial implants. There was a strong correlation between the degree of biomaterial-mediated inflammatory responses and number of recruited cancer cells. Inflammation-mediated cancer cell migration was inhibited by small molecule inhibitors of CXCR4 but not by neutralizing antibody against CCL21. Using chemokine-releasing scaffolds, further studies were carried out to explore the possibility of enhancing cancer cell recruitment. Interestingly, erythropoietin (EPO) releasing scaffolds, but not stromal cell-derived factor-1α-releasing scaffolds, were found to accumulate substantially more melanoma cells than controls. Rather unexpectedly, perhaps by indirectly reducing circulating cancer cells, mice implanted with EPO-releasing scaffolds had ~30% longer life span than other groups. These results suggest that chemokine-releasing scaffolds may potentially function as implantable cancer traps and serve as powerful tools for studying cancer distraction and even selective annihilation of circulating metastatic cancer cells.

PubMed Disclaimer

Figures

Figure 1
Figure 1
Foreign body reactions trigger tumor cell migration. Pre-existing 1-day old subcutaneous implants were found to attract the immigration of CD11b+ inflammatory cells (A, left) and intraperitoneally transplanted B16F10 melanoma cells (A, right). To determine the influence of inflammatory signals in cancer cell migration, varying degrees of inflammatory stimuli intensities were stimulated from 6 hours to 2 weeks according to the experimental time table (B). We found that large numbers of CD11b+ inflammatory cells were recruited to the implantation sites in 12 hours and the influx of inflammatory cells was slowed down after that. These results depict different stages of biomaterial-mediated inflammatory responses (C). The stages of inflammatory responses also affect the extent of melanoma cell recruitment (D).Melanoma cell accumulation in the implant area reached a peak around 24 hours post microsphere implantation (E). Inflammation-induced cancer metastasis is also detected in optical imaging method by labeling melanoma cells with Kodak X-Sight 761 near infrared nanospheres (F).
Figure 2
Figure 2
Immunohistochemical staining of subcutaneous tissues surrounding the PLA microspheres with or without the treatment of dexamethasone (Dex). The accumulation of inflammatory cell (CD11b+) in tissue implanted with PLA microspheres (A, top left) or PLA microspheres soaked with dexamethansone (A, top right) can be observed (200X). The recruitment of melanoma cells (HMB45+) was also observed in tissues implantedwith PLA microspheres (A, bottom left) or dexamethansone embedded PLA microspheres (A, bottom right) (400X). Quantification of the numbers of inflammatory cells and melanoma cells in the subcutaneous tissues with both treatments were graphed and statistically analyzed (B). Data are mean ± SD (n = 6 per group). *P< 0.05, t-test.
Figure 3
Figure 3
Extent of foreign body responses and melanoma cell recruitment to different biomaterial implants. Immunohistochemistry staining of the tissue was carried out to assess the degree of foreign body reactions and quantify the accumulation of CD11b+ inflammatory cells and HMB45+ melanoma cells surround the implants, including PLA, aluminum hydroxide and Glasperlen (A). The quantification analysis of cell recruitment was graphed (B) and the correlation between the melanoma cell numbers and inflammatory cell numbers in surrounding tissue of implanted microspheres statistically analyzed (C). Data are mean ± SD (n = 5 per group). *P< 0.05, ANOVA.
Figure 4
Figure 4
Biodistribution evaluation of B16F10 cell recruitment to the microsphere implant area based on immunohistological analyses. To observe the biodistribution, GFP expressing B16F10 cells were administered intraperitoneally 24 hours following PLA microsphere implantation. High densities of cancer cells were found in the lymph nodes, spleen and implantation area. However, relatively low densities of cancer cells were found in skin, lung, liver, and kidney.
Figure 5
Figure 5
Cancer cell recruitment in response to inflammatory stimulus is universal in different cancer cell types, including Lewis lung cancer, human MDA-MB231 breast cancer, human PC-3 prostate cancer, rat and JHU-31 prostate cancer. Animal bearing PLA implant transplanted with non-labeled cancer cells served as control.
Figure 6
Figure 6
AMD3100 treatment inhibited the cell recruitment of B16F10 melanoma to the implant site (A). However, AMD 3100 blockage exerted no effect on the accumulation of melanoma cells in lymph node (B). On the other hand, CCR7/CCL21 pathway in B16F10 melanoma cell accumulation in the inflamed sites was also examined by CCL21 neutralizing antibody treatments. In contrast, the number of tumor cells migration to microsphere implantation site was not affected (C). However, the presence of B16F10 melanoma cells in the lymph node drastically diminished (D). *P< 0.05, t-test.
Figure 7
Figure 7
EPO and SDF-1α loaded tissue scaffold along with control scaffolds were tested for their melanoma recruitment ability using our murine melanoma metastasis model. Real time in vivo imaging showed accumulation of labeled B16F10 melanoma cells around the tissue scaffolds (A). EPO-releasing tissue scaffolds showed enhanced >1 fold accumulation of melanoma cells detected using Kodak imaging system (B). EPO-releasing scaffolds significantly enhanced the life span of cancer bearing animals (C). *P< 0.05, t-test
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Chambers AF, Groom AC, MacDonald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–572. - PubMed
    1. Fidler IJ. The pathogenesis of cancer metastasis: the ‘seed and soil’ hypothesis revisited. Nat Rev Cancer. 2003;3:453–458. - PubMed
    1. Welch DR. Technical considerations for studying cancer metastasis in vivo. Clin Exp Metastasis. 1997;15:272–306. - PubMed
    1. Gupta GP, Perk J, Acharyya S, de Candia P, Mittal V, Todorova-Manova K, et al. ID genes mediate tumor reinitiation during breast cancer lung metastasis. Proc Natl Acad Sci U S A. 2007;104:19506–19511. - PMC - PubMed
    1. Yamamoto M, Kikuchi H, Ohta M, Kawabata T, Hiramatsu Y, Kondo K, et al. TSU68 prevents liver metastasis of colon cancer xenografts by modulating the premetastatic niche. Cancer Res. 2008;68:9754–9762. - PubMed

Publication types