Abstract
The survival of cancer stem cells is usually limited to a specific tumor microenvironment, and this microenvironment plays a vital role in the development of tumors. The mechanical properties of the microenvironment differ in different regions of solid tumors. However, in solid tumors, whether the distribution of cancer stem cells relates to the mechanical microenvironment of different regions is still unclear. In this study, we undertook a biophysical and biochemical assessment of the changes in the mechanical properties of liver tissue during the progression of liver cancer and explored the distribution of liver cancer stem cells in liver cancer tissues. Our analysis confirmed previous observations that the stiffness of liver tissue gradually increased with the progress of fibrosis. In liver cancer tissues, we found obvious mechanical heterogeneity: the core of the tumor was soft, the invasive front tissue was the hardest, and the para-cancer tissue was in an intermediate state. Interestingly, the greatest number of liver cancer stem cells was found in the invasive front part of the tumor. We finally established that stroma stiffness correlated with the number of liver cancer stem cells. These findings indicate that the distribution of liver cancer stem cells correlates with the mechanical heterogeneity of liver cancer tissue. This result provides a theoretical basis for the development of targeted therapies against the mechanical microenvironment of liver cancer stem cells.
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References
Acerbi I, Cassereau L, Dean I, Shi Q, Au A, Park C, Chen YY, Liphardt J, Hwang ES, Weaver VM (2015) Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol (Camb) 7(10):1120–1134. https://doi.org/10.1039/c5ib00040h
Baiocchini A, Montaldo C, Conigliaro A, Grimaldi A, Correani V, Mura F, Ciccosanti F, Rotiroti N, Brenna A, Montalbano M, D’Offizi G, Capobianchi MR, Alessandro R, Piacentini M, Schininà ME, Maras B, Del Nonno F, Tripodi M, Mancone C (2016) Extracellular matrix molecular remodeling in human liver fibrosis evolution. PLoS ONE 11(3):e0151736. https://doi.org/10.1371/journal.pone.0151736
Barnes JM, Kaushik S, Bainer RO, Sa JK, Woods EC, Kai F, Przybyla L, Lee M, Lee HW, Tung JC, Maller O, Barrett AS, Lu KV, Lakins JN, Hansen KC, Obernier K, Alvarez-Buylla A, Bergers G, Phillips JJ, Nam DH, Bertozzi CR, Weaver VM (2018) A tension-mediated glycocalyx-integrin feedback loop promotes mesenchymal-like glioblastoma. Nat Cell Biol 20(10):1203–1214. https://doi.org/10.1038/s41556-018-0183-3
Broders-Bondon F, Nguyen Ho-Bouldoires TH, Fernandez-Sanchez ME, Farge E (2018) Mechanotransduction in tumor progression: the dark side of the force. J Cell Biol 217(5):1571–1587. https://doi.org/10.1083/jcb.201701039
Chang L, Azzolin L, Di Biagio D, Zanconato F, Battilana G, Lucon Xiccato R, Aragona M, Giulitti S, Panciera T, Gandin A, Sigismondo G, Krijgsveld J, Fassan M, Brusatin G, Cordenonsi M, Piccolo S (2018) The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563(7730):265–269. https://doi.org/10.1038/s41586-018-0658-1
Chen J, Li Y, Yu TS, McKay RM, Burns DK, Kernie SG, Parada LF (2012) A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 488(7412):522–526. https://doi.org/10.1038/nature11287
Chen Q, Yang D, Zong H, Zhu L, Wang L, Wang X, Zhu X, Song X, Wang J (2017) Growth-induced stress enhances epithelial-mesenchymal transition induced by IL-6 in clear cell renal cell carcinoma via the Akt/GSK-3β/β-catenin signaling pathway. Oncogenesis 6(8):e375. https://doi.org/10.1038/oncsis.2017.74
Cheng Z, Li X, Ding J (2016) Characteristics of liver cancer stem cells and clinical correlations. Cancer Lett 379(2):230–238. https://doi.org/10.1016/j.canlet.2015.07.041
Cross SE, Jin YS, Rao J, Gimzewski JK (2007) Nanomechanical analysis of cells from cancer patients. Nat Nanotechnol 2(12):780–783. https://doi.org/10.1038/nnano.2007.388
Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126(4):677–689. https://doi.org/10.1016/j.cell.2006.06.044
Gang Z, Qi Q, Jing C, Wang C (2009) Measuring microenvironment mechanical stress of rat liver during diethylnitrosamine induced hepatocarcinogenesis by atomic force microscope. Microsc Res Tech 72(9):672–678. https://doi.org/10.1002/jemt.20716
Glentis A, Oertle P, Mariani P, Chikina A, El Marjou F, Attieh Y, Zaccarini F, Lae M, Loew D, Dingli F, Sirven P, Schoumacher M, Gurchenkov BG, Plodinec M, Vignjevic DM (2017) Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat Commun 8(1):924. https://doi.org/10.1038/s41467-017-00985-8
Hwang PY, Brenot A, King AC, Longmore GD, George SC (2019) Randomly distributed K14+ breast tumor cells polarize to the leading edge and guide collective migration in response to chemical and mechanical environmental cues. Cancer Res 79(8):1899–1912. https://doi.org/10.1158/0008-5472.CAN-18-2828
Kaseb HO, Fohrer-Ting H, Lewis DW, Lagasse E, Gollin SM (2016) Identification, expansion and characterization of cancer cells with stem cell properties from head and neck squamous cell carcinomas. Exp Cell Res 348(1):75–86. https://doi.org/10.1016/j.yexcr.2016.09.003
Kaul-Ghanekar R, Singh S, Mamgain H, Jalota-Badhwar A, Paknikar KM, Chattopadhyay S (2009) Tumor suppressor protein SMAR1 modulates the roughness of cell surface: combined AFM and SEM study. BMC Cancer 9:350. https://doi.org/10.1186/1471-2407-9-350
Lashen SA, Elshafei MM, Hablass FH, Alsayed EA, Hassan AA (2020) Liver stiffness as a predictor of hepatocellular carcinoma behavior in patients with hepatitis C related liver cirrhosis. Hepatobiliary Pancreat Dis Int 19(1):22–28. https://doi.org/10.1016/j.hbpd.2019.11.004
Lekka M, Gil D, Pogoda K, Dulińska-Litewka J, Jach R, Gostek J, Klymenko O, Prauzner-Bechcicki S, Stachura Z, Wiltowska-Zuber J, Okoń K, Laidler P (2012) Cancer cell detection in tissue sections using AFM. Arch Biochem Biophys 518(2):151–156. https://doi.org/10.1016/j.abb.2011.12.013
Li SC, Vu LT, Luo JJ, Zhong JF, Li Z, Dethlefs BA, Loudon WG, Kabeer MH (2017) Tissue elasticity bridges cancer stem cells to the tumor microenvironment through microRNAs: Implications for a “Watch-and-Wai” approach to cancer. Curr Stem Cell Res Ther 12(6):455–470. https://doi.org/10.2174/1574888X12666170307105941
Li X, Das A, Bi D (2019a) Mechanical heterogeneity in tissues promotes rigidity and controls cellular invasion. Phys Rev Lett 123(5):058101. https://doi.org/10.1103/PhysRevLett.123.058101
Li Y, Wei Y, Tang W, Luo J, Wang M, Lin H, Guo H, Ma Y, Zhang J, Li Q (2019b) Association between the degree of fibrosis in fibrotic focus and the unfavorable clinicopathological prognostic features of breast cancer. PeerJ 7:e8067. https://doi.org/10.7717/peerj.8067
Li M, Xi N, Wang YC, Liu LQ (2020) Atomic force microscopy for revealing micro/nanoscale mechanics in tumor metastasis: from single cells to microenvironmental cues. Acta Pharmacol Sin. https://doi.org/10.1038/s41401-020-0494-3.10.1038/s41401-020-0494-3
Liu C, Pei H, Tan F (2020a) Matrix stiffness and colorectal cancer. Onco Targets Ther 13:2747–2755. https://doi.org/10.2147/OTT.S231010
Liu Q, Luo Q, Ju Y, Song G (2020b) Role of the mechanical microenvironment in cancer development and progression. Cancer Biol Med 17(2):282–292. https://doi.org/10.20892/j.issn.2095-3941.2019.0437
Lopez JI, Kang I, You WK, McDonald DM, Weaver VM (2011) In situ force mapping of mammary gland transformation. Integr Biol (Camb) 3(9):910–921. https://doi.org/10.1039/c1ib00043h
Luo Q, Kuang D, Zhang B, Song G (2016) Cell stiffness determined by atomic force microscopy and its correlation with cell motility. Biochim Biophys Acta 1860(6):1953–1960. https://doi.org/10.1016/j.bbagen.2016.06.010
Magee JA, Piskounova E, Morrison SJ (2012) Cancer stem cells: impact, heterogeneity, and uncertainty. Cancer Cell 21(3):283–296. https://doi.org/10.1016/j.ccr.2012.03.003
Najafi M, Mortezaee K, Majidpoor J (2019) Cancer stem cell (CSC) resistance drivers. Life Sci 234:116781. https://doi.org/10.1016/j.lfs.2019.116781
Omar R, Yang J, Liu H, Davies NM, Gong Y (2016) Hepatic stellate cells in liver fibrosis and siRNA-Based therapy. Rev Physiol Biochem Pharmacol 172:1–37. https://doi.org/10.1007/112_2016_6
Oudin MJ, Weaver VM (2016) Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis. Cold Spring Harb Symp Quant Biol 81:189–205. https://doi.org/10.1101/sqb.2016.81.030817
Pang MF, Siedlik MJ, Han S, Stallings-Mann M, Radisky DC, Nelson CM (2016) Tissue stiffness and hypoxia modulate the integrin-linked kinase ILK to control breast cancer stem-like cells. Cancer Res 76(18):5277–5287. https://doi.org/10.1158/0008-5472.CAN-16-0579
Papalazarou V, Salmeron-Sanchez M, Machesky LM (2018) Tissue engineering the cancer microenvironment-challenges and opportunities. Biophys Rev 10(6):1695–1711. https://doi.org/10.1007/s12551-018-0466-8
Plodinec M, Loparic M, Monnier CA, Obermann EC, Zanetti-Dallenbach R, Oertle P, Hyotyla JT, Aebi U, Bentires-Alj M, Lim RY, Schoenenberger CA (2012) The nanomechanical signature of breast cancer. Nat Nanotechnol 7(11):757–765. https://doi.org/10.1038/nnano.2012.167
Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR (2012) Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21(3):418–429. https://doi.org/10.1016/j.ccr.2012.01.007
Ruiz-Ontañon P, Orgaz JL, Aldaz B, Elosegui-Artola A, Martino J, Berciano MT, Montero JA, Grande L, Nogueira L, Diaz-Moralli S, Esparís-Ogando A, Vazquez-Barquero A, Lafarga M, Pandiella A, Cascante M, Segura V, Martinez-Climent JA, Sanz-Moreno V, Fernandez-Luna JL (2013) Cellular plasticity confers migratory and invasive advantages to a population of glioblastoma-initiating cells that infiltrate peritumoral tissue. Stem Cells (Dayton, Ohio) 31(6):1075–1085. https://doi.org/10.1002/stem.1349
Saneyasu T, Akhtar R, Sakai T (2016) Molecular cues guiding matrix stiffness in liver fibrosis. Biomed Res Int 2016:2646212. https://doi.org/10.1155/2016/2646212
Schwitalla S, Fingerle AA, Cammareri P, Nebelsiek T, Göktuna SI, Ziegler PK, Canli O, Heijmans J, Huels DJ, Moreaux G, Rupec RA, Gerhard M, Schmid R, Barker N, Clevers H, Lang R, Neumann J, Kirchner T, Taketo MM, van den Brink GR, Sansom OJ, Arkan MC, Greten FR (2013) Intestinal tumorigenesis initiated by dedifferentiation and acquisition of stem-cell-like properties. Cell 152(1–2):25–38. https://doi.org/10.1016/j.cell.2012.12.012
Sokolović A, Sokolović M, Boers W, Elferink RP, Bosma PJ (2010) Insulin-like growth factor binding protein 5 enhances survival of LX2 human hepatic stellate cells. Fibrogenesis Tissue Repair 3:3. https://doi.org/10.1186/1755-1536-3-3
Song L, Zhang JG, Zheng L, Feng X, Hou J, Zhang HL, Liu SF (2020) Establishment of rat liver cancer cell lines with different metastatic potential. Sci Rep 10(1):8329. https://doi.org/10.1038/s41598-020-65338-w
Sun J, Luo Q, Liu L, Song G (2016) Liver cancer stem cell markers: progression and therapeutic implications. World J Gastroenterol 22(13):3547–3557. https://doi.org/10.3748/wjg.v22.i13.3547
Sun J, Luo Q, Liu L, Song G (2019) Low-level shear stress induces differentiation of liver cancer stem cells via the Wnt/β-catenin signalling pathway. Exp Cell Res 375(1):90–96. https://doi.org/10.1016/j.yexcr.2018.12.023
Tan F, Huang Y, Pei Q, Liu H, Pei H, Zhu H (2018) Matrix stiffness mediates stemness characteristics via activating the Yes-associated protein in colorectal cancer cells. J Cell Biochem. https://doi.org/10.1002/jcb.27532.10.1002/jcb.27532
Triantafillu UL, Park S, Klaassen NL, Raddatz AD, Kim Y (2017) Fluid shear stress induces cancer stem cell-like phenotype in MCF7 breast cancer cell line without inducing epithelial to mesenchymal transition. Int J Oncol 50(3):993–1001. https://doi.org/10.3892/ijo.2017.3865
Tse JM, Cheng G, Tyrrell JA, Wilcox-Adelman SA, Boucher Y, Jain RK, Munn LL (2012) Mechanical compression drives cancer cells toward invasive phenotype. Proc Natl Acad Sci U S A 109(3):911–916. https://doi.org/10.1073/pnas.1118910109
Tung JC, Barnes JM, Desai SR, Sistrunk C, Conklin MW, Schedin P, Eliceiri KW, Keely PJ, Seewaldt VL, Weaver VM (2015) Tumor mechanics and metabolic dysfunction. Free Radic Biol Med 79:269–280. https://doi.org/10.1016/j.freeradbiomed.2014.11.020
Wang J, Xu SL, Duan JJ, Yi L, Guo YF, Shi Y, Li L, Yang ZY, Liao XM, Cai J, Zhang YQ, Xiao HL, Yin L, Wu H, Zhang JN, Lv SQ, Yang QK, Yang XJ, Jiang T, Zhang X, Bian XW, Yu SC (2019) Invasion of white matter tracts by glioma stem cells is regulated by a NOTCH1-SOX2 positive-feedback loop. Nat Neurosci 22(1):91–105. https://doi.org/10.1038/s41593-018-0285-z
Wei SC, Yang J (2016) Forcing through tumor metastasis: the interplay between tissue rigidity and epithelial-mesenchymal transition. Trends Cell Biol 26(2):111–120. https://doi.org/10.1016/j.tcb.2015.09.009
Wong GS, Rustgi AK (2013) Matricellular proteins: priming the tumour microenvironment for cancer development and metastasis. Br J Cancer 108(4):755–761. https://doi.org/10.1038/bjc.2012.592
Yang N, Chen T, Wang L, Liu R, Niu Y, Sun L, Yao B, Wang Y, Yang W, Liu Q, Tu K, Liu Z (2020) CXCR4 mediates matrix stiffness-induced downregulation of UBTD1 driving hepatocellular carcinoma progression via YAP signaling pathway. Theranostics 10(13):5790–5801. https://doi.org/10.7150/thno.44789
Ye J, Wu D, Wu P, Chen Z, Huang J (2014) The cancer stem cell niche: cross talk between cancer stem cells and their microenvironment. Tumour Biol 35(5):3945–3951. https://doi.org/10.1007/s13277-013-1561-x
Yoshino H, Futakuchi M, Cho YM, Ogawa K, Takeshita F, Imai N, Tamano S, Shirai T (2005) Modification of an in vivo lung metastasis model of hepatocellular carcinoma by low dose N-nitrosomorpholine and diethylnitrosamine. Clin Exp Metastasis 22(5):441–447. https://doi.org/10.1007/s10585-005-2807-9
Yu W, Sharma S, Gimzewski JK, Rao J (2017) Nanocytology as a potential biomarker for cancer. Biomark Med 11(3):213–216. https://doi.org/10.2217/bmm-2017-0019
Zhang R, Ma M, Dong G, Yao RR, Li JH, Zheng QD, Dong YY, Ma H, Gao DM, Cui JF, Ren ZG, Chen RX (2017) Increased matrix stiffness promotes tumor progression of residual hepatocellular carcinoma after insufficient heat treatment. Cancer Sci 108(9):1778–1786. https://doi.org/10.1111/cas.13322
Acknowledgements
This work was supported by grants from National Natural Science Foundation of China (11832008, 11772073 and 31700810), Fundamental Research Funds for the Central Universities (2020CDJ-LHZZ-028/029), Natural Science Foundation of Chongqing (cstc2020jcyj-msxmX0545), Program of Postgraduate Tutor Team of Chongqing Education Commission (2018).
Funding
National Natural Science Foundation of China, Grant Numbers: 11832008, 11772073, 31700810; Fundamental Research Funds for the Central Universities, Grant Number: 2020CDJ-LHZZ-028/029; Natural Science Foundation of Chongqing, Grant Number: cstc2020jcyj-msxmX0545; Program of Postgraduate Tutor Team of Chongqing Education Commission, Grant Number: 2018.
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YS performed the experiments, analyzed the data, and wrote the manuscript. HL carried out the experiments. QC performed data processing and statistical analysis. QL and GS designed the study, supervised the experiments, and wrote the manuscript.
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Sun, Y., Li, H., Chen, Q. et al. The distribution of liver cancer stem cells correlates with the mechanical heterogeneity of liver cancer tissue. Histochem Cell Biol 156, 47–58 (2021). https://doi.org/10.1007/s00418-021-01979-w
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DOI: https://doi.org/10.1007/s00418-021-01979-w