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Int J Biol Sci 2022; 18(10):3993-4005. doi:10.7150/ijbs.72552 This issue Cite

Research Paper

Spatiotemporal quantification of metastatic tumour cell growth and distribution in lymph nodes by whole-mount tissue 3D imaging

Jun Li^1#, Chun-Jie Xu^2#, Guang-Ang Tian^1,3#, Qing Li^1#, Dong-Xue Li^1#, Fang Yan⁴, Yao-Qi Zhou¹, Pei-Qi Huang¹, Jia-Xuan Xie¹, Xu Wang¹, Shu-Heng Jiang¹, Ya-Hui Wang¹, Jian Song⁵, Xue-Li Zhang¹, Shuang-Qin Yi⁶, Li-Peng Hu^1✉, Qing Xu^2✉, Xiao-Wei Li^4✉, Zhi-Gang Zhang^1✉

1. State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
2. Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
3. Department of Central Laboratory, Shanghai Chest Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
4. School of Biomedical Engineering, Shanghai Jiao Tong University, Shanghai, China.
5. Department of Radiation Oncology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
6. Department of Frontier Health Sciences, Graduate School of Human Health Sciences, Tokyo Metropolitan University, Japan.
#Contributed equally to this work.

✉ Corresponding authors: Li-Peng Hu, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Qing Xu, Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, 160 Pujian Road, Shanghai 200127, China. Xiao-Wei Li, School of Biomedical Engineering, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. Zhi-Gang Zhang, State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, 800 Dongchuan Road, Shanghai 200240, China. E-mail addresses: lphuorg (L.P. Hu); renjixuqingcom (Q. Xu); xl3aedu.cn (X.W. Li); zzhangorg (Z.Z. Zhang). More

Abstract

Lymph nodes (LNs) are a common site of metastasis in many solid cancers. Tumour cells can migrate to LNs for further metastatic colonization of distant organs, indicating poor prognosis and requiring different clinical interventions. The histopathological diagnostic methods currently used to detect clinical lymph node metastasis (LNM) have limitations, such as incomplete visualization. To obtain a complete picture of metastatic LNs on the spatial and temporal scales, we used ultimate 3D imaging of solvent-cleared organs (uDISCO) and 3D rapid immunostaining. MC38 cells labelled with EGFP were injected into the left footpads of C57BL/6 mice. Draining lymph nodes (DLNs) harvested from these mice were cleared using the uDISCO method. Metastatic colorectal cancer (CRC) cells in various regions of DLNs from mice at different time points were quantified using 3D imaging of whole-mount tissue. Several stages of tumour cell growth and distribution in LNs were identified: 1) invasion of lymphatic vessels (LVs) and blood vessels (BVs); 2) dispersion outside LVs and BVs for proliferation and expansion; and 3) re-entry into BVs and efferent lymphatic vessels (ELVs) for further distant metastasis. Moreover, these data demonstrated that mouse fibroblast cells (MFCs) could not only promote LNM of tumour cells but also metastasize to LNs together with tumour cells, thus providing a “soil” for tumour cell colonization. In conclusion, 3D imaging of whole-mount tissue and spatiotemporal analysis of LNM may collectively constitute an auxiliary method to improve the accuracy of clinical LNM detection.

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