Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy

Egeblad, Mikala; Ewald, Andrew J.; Askautrud, Hanne A.; Truitt, Morgan; Welm, Bryan E.; Bainbridge, Emma; Peeters, G; Krummel, Matthew F.; Werb, Zena

doi:10.1242/dmm.000596

Cited by 181 publications

(224 citation statements)

References 59 publications

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“…However, breast cancer also involves characteristic changes in the ECM and the tumor microenvironment (9)(10)(11)(12). For example, collagen I is enriched and aligned at the stromal border in breast tumors (10,13), changes in collagen I organization are independent negative prognostic indicators (14), and increased collagen I crosslinking accelerates progression in experimental cancer models (15).…”

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confidence: 99%

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

Nguyen-Ngoc

Cheung

Brenot

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Breast cancer progression involves genetic changes and changes in the extracellular matrix (ECM). To test the importance of the ECM in tumor cell dissemination, we cultured epithelium from primary human breast carcinomas in different ECM gels. We used basement membrane gels to model the normal microenvironment and collagen I to model the stromal ECM. In basement membrane gels, malignant epithelium either was indolent or grew collectively, without protrusions. In collagen I, epithelium from the same tumor invaded with protrusions and disseminated cells. Importantly, collagen I induced a similar initial response of protrusions and dissemination in both normal and malignant mammary epithelium. However, dissemination of normal cells into collagen I was transient and ceased as laminin 111 localized to the basal surface, whereas dissemination of carcinoma cells was sustained throughout culture, and laminin 111 was not detected. Despite the large impact of ECM on migration strategy, transcriptome analysis of our 3D cultures revealed few ECM-dependent changes in RNA expression. However, we observed many differences between normal and malignant epithelium, including reduced expression of cell-adhesion genes in tumors. Therefore, we tested whether deletion of an adhesion gene could induce sustained dissemination of nontransformed cells into collagen I. We found that deletion of P-cadherin was sufficient for sustained dissemination, but exclusively into collagen I. Our data reveal that metastatic tumors preferentially disseminate in specific ECM microenvironments. Furthermore, these data suggest that breaks in the basement membrane could induce invasion and dissemination via the resulting direct contact between cancer cells and collagen I.

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confidence: 99%

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

Nguyen-Ngoc

Cheung

Brenot

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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391

375

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“…Using color-coded imaging of the TME, Egeblad et al observed that regulatory Tlymphocytes migrated to blood vessels. These authors observed that stromal cells had higher motility in the TME at the tumor periphery than within the tumor mass (22).…”

Section: Imaging the Critical Role Of Stromal Cells In Metastasismentioning

confidence: 95%

“…Color-coded imaging of the TME has enabled important discoveries of its cellular components (22,23). Using color-coded imaging of the TME, Egeblad et al observed that regulatory Tlymphocytes migrated to blood vessels.…”

Section: Imaging the Critical Role Of Stromal Cells In Metastasismentioning

confidence: 99%

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

Suetsugu

Shimizu

Saji

et al. 2018

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Abstract. The tumor microenvironment (TME) contains stromal cells in a complex interaction with cancer cells. This relationship has become better understood with the use of fluorescent proteins for in vivo imaging cancer-cell or stromal-cell targeting by potential therapeutics can be visualized. Color-coded imaging enabled the visualization of apparent fusion of cancer and stromal cells. Color-coded imaging is a powerful tool visualizing the interaction of cancer and stromal cells during cancer progression and treatment.In vivo imaging with fluorescent proteins was pioneered by our laboratories and has been particularly useful for studying tumor growth, invasion, cancer-cell trafficking, metastasis, angiogenesis, and other aspects of tumor progression (1-5). Multicolored proteins have allowed the color-coding of cancer cells growing in vivo such as between highly-and poorly-metastatic cells, cancer stem and non-stem cells, and gene transfer between cancer cells (3, 4,(6)(7)(8)(9)(10)(11)(12)(13).The present review focuses on color-coded imaging of cancer and stromal cells in the tumor microenvironment (TME).Transgenic nude mice expressing fluorescent proteins for colorcode imaging of the TME. The green fluorescent protein (GFP)-expressing athymic nude mouse was obtained by crossing nontransgenic nude mice with the transgenic C57/B6 GFP mouse in which the β-actin promoter drives GFP. In the adult GFP nude mice, most organs brightly expressed GFP, including the heart, lungs, spleen, pancreas, esophagus, stomach, duodenum, and the entire digestive system from the tongue to the anus; the male and female reproductive systems; brain and spinal cord; and the circulatory system, including the heart and major arteries and veins. The bared skeleton also highly expressed GFP (14).

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“…(130-132) Different components of tumor stroma similarly affect the progression of the tumor. As tumors develop and progress, they undergo dramatic morphological changes (133,134), which also involves the stroma (133,(135)(136)(137). The importance of stage-specific changes of the stroma is not yet completely comprehensible.…”

Section: Csc Conceptmentioning

confidence: 99%

Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

Meiliana

Dewi²,

Wijaya

2016

Indones Biomed J

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BACKGROUND: Cancer is a disease of genomic instability, evasion of immune cells, and adaptation of the tumor cells to the changing environment. Genetic heterogeneity caused by tumors and tumor microenvironmental factors forms the basis of aggressive behavior of some cancer cell populations.CONTENT: Cancers arise in self-renewing cell populations and that the resulting cancers, like their normal organ counterparts, are composed of hierarchically organized cell populations. Self – renewing “cancer stem cells” (CSC) maintain tumor growth and generate the diverse populations constituting the tumor bulk. CSCs in multiple tumor types have been demonstrated to be relatively resistant to radiation and chemotherapy. The clinical relevance of these studies has been supported by neoadjuvant breast cancer trials that demonstrated increases in the proportions of CSCs after therapy. The CSC hypothesis has tremendously important clinical implications.SUMMARY: In summary, a large and accumulating body of evidence supports the CSC hypothesis, which has important implications for cancer prevention and therapy. The ultimate test of this hypothesis will require clinical trials demonstrating that targeting of these pathways reduces cancer incidence and improves outcomes for patients with cancer.KEYWORDS: Somatic mutation, tumor heterogeneity, metastasis, epithelial-mesenchymal transition, CSC niche

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Visualizing stromal cell dynamics in different tumor microenvironments by spinning disk confocal microscopy

Cited by 181 publications

References 59 publications

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

ECM microenvironment regulates collective migration and local dissemination in normal and malignant mammary epithelium

Visualizing the Tumor Microenvironment by Color-coded Imaging in Orthotopic Mouse Models of Cancer

Cancer Stem Cell Hypothesis: Implication for Cancer Prevention and Treatment

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