Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Sogawa, Chiharu; Eguchi, Takanori; Namba, Yuri; Okusha, Yuka; Aoyama, Eriko; Ohyama, Kazumi; Okamoto, Kuniaki

doi:10.3390/cells10020344

Cited by 24 publications

(15 citation statements)

References 58 publications

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“…Cisplatin concentrations leading to 50% inhibition of cultures’ growth in the collagen hydrogel differed by an order of magnitude (about 8 μM for SKOV3.ip-kat, and more than 80 μM for A431-GFP). Our data on the increased resistance of tumor cells cultured in 3D in vitro models compared to monolayer are in line with the results of other studies [ 54 , 55 , 56 ]. Such stability may be caused by interaction of extracellular matrix molecules with cell surface receptors.…”

Section: Discussionsupporting

confidence: 92%

Real-Time Fluorescence Visualization and Quantitation of Cell Growth and Death in Response to Treatment in 3D Collagen-Based Tumor Model

Sencha

Dobrynina

Pospelov

et al. 2022

IJMS

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The use of 3D in vitro tumor models has become a common trend in cancer biology studies as well as drug screening and preclinical testing of drug candidates. The transition from 2D to 3D matrix-based cell cultures requires modification of methods for assessing tumor growth. We propose the method for assessing the growth of tumor cells in a collagen hydrogel using macro-scale registration and quantification of the gel epi-fluorescence. The technique does not require gel destruction, can be used for real-time observation of fast (in seconds) cellular responses and demonstrates high agreement with cell counting approaches or measuring total DNA content. The potency of the method was proven in experiments aimed at testing cytotoxic activity of chemotherapeutic drug (cisplatin) and recombinant targeted toxin (DARPin-LoPE) against two different tumor cell lines genetically labelled with fluorescent proteins. Moreover, using fluorescent proteins with sensor properties allows registration of dynamic changes in cells’ metabolism, which was shown for the case of sensor of caspase 3 activity.

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Section: Discussionsupporting

confidence: 92%

Real-Time Fluorescence Visualization and Quantitation of Cell Growth and Death in Response to Treatment in 3D Collagen-Based Tumor Model

Sencha

Dobrynina

Pospelov

et al. 2022

IJMS

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“…LuM-1 is a highly aggressive and non-immunogenic subclone of colon 26 48 , and metformin alone did not show significant anti-tumor effects on sc tumors or lung metastases. However, synergistic effects of RT and metformin were observed.…”

Section: Discussionmentioning

confidence: 92%

Metformin combined with local irradiation provokes abscopal effects in a murine rectal cancer model

Tojo

Miyato

Koinuma

et al. 2022

Sci Rep

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Although preoperative chemoradiation therapy can down-stage locally advanced rectal cancer (LARC), it has little effect on distant metastases. Metformin exerts an anti-cancer effect partly through the activation of host immunity. LuM1, a highly lung metastatic subclone of colon 26, was injected subcutaneously (sc) in BALB/c mice and treated with metformin and/or local radiation (RT). Lung metastases and the primary tumors were evaluated and the phenotypes of immune cells in the spleen and lung metastases were examined with flow cytometry and immunohistochemistry. Local RT, but not metformin, partially delayed the growth of sc tumor which was augmented with metformin. Lung metastases were unchanged in metformin or RT alone, but significantly reduced in the combined therapy. The ratios of splenic T cells tended to be low in the RT group, which were increased by the addition of metformin. IFN-γ production of the splenic CD4(+) and CD8(+) T cells was enhanced and CD49b (+) CD335(+) activated NK cells was increased after combined treatment group. Density of NK cells infiltrating in lung metastases was increased after combination treatment. Metformin effectively enhances local and abscopal effects of RT though the activation of cell-mediated immunity and might be clinically useful for LARC.

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“…As for the validation data set, we next confirmed whether the significant DEGs in PDSs shared with the stroma isolated from other cancer. It has been shown that oral cancer and colorectal cancer (CRC) have a common gene expression profile and therapeutic target (29,30). Therefore, we additionally analyzed the publicly available expression profile of PDS of CRC, for which the isolation method of stromal cells was used similar to our method.…”

Section: Cellular Chemotaxis Factor Ccl2 Is Highly Expressed In Patient-derived Stromal Cellsmentioning

confidence: 99%

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment

Oo¹,

Kawai²,

Takabatake³

et al. 2022

JCI Insight

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Accumulating evidence has shown that cancer stroma and bone marrow-derived cells (BMDCs) in the tumor microenvironment (TME) play vital roles in tumor progression. However, the mechanism by which oral cancer stroma recruits any particular subset of BMDCs remains largely unknown. Here we sought to identify the subset of BMDCs that is recruited by cancer stroma. We established a sequential transplantation model in BALB/c nude mice, including (i) bone marrow transplantation of GFP-expressing cells and (ii) co-xenografting of patient-derived stroma (two cases, designated PDS1 and PDS2) with oral cancer cells (HSC-2). As controls, xenografting was performed with HSC-2 alone or in combination with normal human dermal fibroblasts (HDF). PDS1, PDS2, and HDF all promoted BMDCs migration in vitro and recruitment in vivo. Multicolor immunofluorescence revealed that the PDS co-xenografts recruited Arginase-1/CD11b/GR1/GFP quadruple-positive cells, which are myeloid-derived suppressor cells (MDSCs), to the TME, whereas the HDF co-xenograft did not.Screening using microarrays revealed that PDS1 and PDS2 expressed CCL2 mRNA (encoding C-C motif chemokine ligand 2) at higher levels than did HDF. Indeed, PDS xenografts contained significantly higher proportions of CCL2-positive stromal cells and CCR2/Arginase-1/CD11b/GR1 quadruple-positive MDSCs (as receiver cells) than the HDF co-xenograft. Consistently, a CCL2 synthesis inhibitor and a CCR2 antagonist significantly inhibited the PDS-driven migration of BM cells in vitro. Furthermore, intraperitoneal injection of the CCR2 antagonist to the PDS xenograft models significantly reduced the CCR2/Arginase-1/CD11b/GR1 quadruple-positive MDSCs infiltration to the TME. In conclusion, oral cancer stroma-secreted CCL2 is a key signal for recruiting CCR2-positive MDSCs from bone marrow to the TME.

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Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Cited by 24 publications

References 58 publications

Real-Time Fluorescence Visualization and Quantitation of Cell Growth and Death in Response to Treatment in 3D Collagen-Based Tumor Model

Real-Time Fluorescence Visualization and Quantitation of Cell Growth and Death in Response to Treatment in 3D Collagen-Based Tumor Model

Metformin combined with local irradiation provokes abscopal effects in a murine rectal cancer model

Resident stroma-secreted chemokine CCL2 governs myeloid-derived suppressor cells in the tumor microenvironment

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