Role of tumor/endothelial cell interactions in tumor growth and metastasis


  • O.N. Pyaskovskaya R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • D.L. Kolesnik R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • L.V. Garmanchouk ESC Institute of Biology and Medicine, Taras Shevchenko National University of Kyiv, Kyiv 01601, Ukraine
  • Yu.V. Yanish R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology
  • G.I. Solyanik R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology



metastatic potential, tumor-endothelial cell interactionsmetastatic potential, tumor-endothelial cell interactions


Summary. Background: It is known that interactions between tumor and endothelial cells have a significant influence on the growth and metastasis of malignant tumors. Aim: To study the reciprocal effect of Lewis lung carcinoma (LLC) and endothelial cells on the growth rate of each other upon their co-cultivation in vitro and to assess the contribution of such tumor/endothelial cell crosstalk to in vivo LLC growth and metastasis. Materials and Methods: Two variants of Lewis lung carcinoma cells, high-metastatic (LLC) and low-metastatic (LLC/R9), and murine aorta endothelial cell line (MAEC) were used. Kinetics of tumor cell growth in vitro and in vivo, electrokinetic properties of tumor cells and their adhesion to endothelial monolayer, and the number of tumor and endothelial viable cells after 1-day contact or non-contact co-cultivation were estimated. Results: LLC/R9 had significantly higher growth rate in vivo (as opposed to in vitro) than LLC. However, the number and volume of lung metastatic lesions in LLC/R9-bearing mice were 4.5-fold (p < 0.05) and 3.6-fold lower (p < 0.05), respectively, compared to those in LLC-bearing mice. Non-contact co-cultivation of LLC/R9 + MAEC caused more than a 34% (p < 0.05) LLC/R9-induced increase in the number of MAEC and a 60% (p < 0.05) MAEC-induced increase in the number of LLC/R9 cells as compared to those of corresponding controls (cells cultured alone). In contrast, in the case of LLC + MAEC, both the number of LLC and MAEC cells after their non-contact co-cultivation and cultivation alone did not differ significantly. Contact co-cultivation LLC+MAEC (in contrast to LLC/R9+MAEC) caused more than a 50% (p < 0.01) LLC-induced decrease in the number of MAEC and a 50% decrease (p < 0.05) MAEC-induced in the number of LLC cells as compared to the corresponding controls. Both tumor cell variants showed a bimodal distribution of cells by ζ-potential, but in the case of LLC there was observed a shift towards high values due to 52% of cells with a surface charge density > 10 C/m2, while in the case of LLC/R9 such a subpopulation was absent and 19% of cells had a surface charge < 5 C/m2. The number of LLC cells that adhered to the monolayer of endothelial cells was by 65% (p < 0.05) higher than that of LLC/R9 cells. Conclusion. Obtained data demonstrated that the tumor/endothelial cell relationships might reflect the features of tumor growth and metastasis of a malignant tumor.


Gupta GP, Massague J. Cancer metastasis: building a framework. Cell 2006; 127: 679–95.

Guan X. Cancer metastases: challenges and opportunities. Acta Pharm Sin B 2015; 5: 402–18.

Seyfried TN, Huysentruyt LC. On the origin of cancer metastasis. Crit Rev Oncol 2013; 18: 43–73.

Valastyan S, Weinberg RA. Tumor metastasis: molecular insights and evolving paradigms. Cell 2011; 147: 275–92.

da Cunha BR, Domingos C, Stefanini ACB, et al. Cellular interactions in the tumor microenvironment: The role of secretome. J Cancer 2019; 10: 4574–87.

López de Andrés J, Griñán-Lisón C, Jiménez G, Marchal JA. Cancer stem cell secretome in the tumor microenvironment: a key point for an effective personalized cancer treatment. J Hematol Oncol 2020; 13: 136.

Fallah A, SadeghiniaA, KahrobaH, et al.Therapeutic targeting of angiogenesis molecular pathways in angiogenesis-dependent diseases. Biomed Pharmacother 2019; 110: 775–85.

Yadav A, Kumar B, Yu J-G, et al. Tumor-associated endothelial cells promote tumor metastasis by chaperoning circulating tumor cells and protecting them from anoikis. PLoS ONE 2015; 10: e0141602.

Maishi N, Hida K. Tumor endothelial cells accelerate tumor metastasis. Cancer Sci 2017; 108: 1921–26.

Maishi N, Ohba, Y, Akiyama K, et al. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. Sci Rep 2016; 6: 28039.

Mierke CT. Role of the endothelium during tumor cell metastasis: is the endothelium a barrier or a promoter for cell invasion and metastasis? J Biophys 2008; 2008: 183516.

Solyanik GI, Pyaskovskaya ON, Garmanchouk LV. Cisplatin-resistant Lewis lung carcinoma cells possess increased level of VEGF secretion. Exp Oncol 2003; 24: 260–5.

Solyanik GI, Fedorchuk A, Pyaskovskaya ON, et al.Anticancer activity of aconitine-containing herbal extract. Exp Oncol 2004; 4: 307–11.

Gumcovski F, Kaminska G, Kaminski M et al.Heterogeneity of mouse vascular endothelium. Bloоd Vessels 1987; 24: 11–23.

Markowska A, Urasińska E, Domagała W. In vitro assessment of adhesion molecules expression by human endothelial cells cocultured with c-erbB2-positive and c-erbB2-negative breast carcinoma cell lines. Pol J Pathol 2008; 59: 49–54.

Kolesnik DL, Garmanchouk LV, Pyaskovskaya ON, Solyanik GI. Interactions between endothelial and tumor cells under their “contact” and “contactless” co-cultivation. Reports of NAS of Ukraine 2009; (10): 167–71 (in Ukrainian).

Wang XQ, Duan XM, Liu LH, et al.Carboxyfluorescein diacetate succinimidyl ester fluorescent dye for cell labeling. Acta Biochim Biophys Sin 2005; 37: 379–85.

Garmanchuk LV, Pyaskovskaya ON, Yahish YuV, et al.Influence of aconitine-containing herbal extract BC1 on proliferative and electrokinetic characteristics of endothelial cells. Exp Oncol 2005; 27: 262–6.

Fedorchuk OG, Pyaskovskaya OM, Skivka LM, et al. Paraneoplastic syndrome in mice bearing high-angiogenic variant of Lewis lung carcinoma: relations with tumor derived VEGF. Cytokine 2012; 57: 81–8.

Pyaskovslaya ON, Yanish YuV, Kolesnik DL, et al.The action of aconitine-containing agent ВС1 on electrokinetic properties of tumor cells Biophys Bull 2008; 21: 35–41 (in Russian).

Pyaskovskaya ON, Sorokina LV, Kolesnik DL, et al.Dynamics of changes of antioxidant system indexes during the growth of two Lewis lung carcinoma variants. Exp Oncol 2014; 36: 29–33.

Kolesnik DL, Pyaskovskaya ON, Tregubova NV, Solyanik GI. Lewis lung carcinoma variant with a high sensitivity to antitumor antiangiogenic therapy exhibits a high capacity for autophagy. Cytol Genet 2012; 46: 155–60.

Pyaskovskaya ON, Dasyukevich OI, Kolesnik DL, et al.Changes in VEGF level and tumor growth characteristics during Lewis lung carcinoma progression towards cis-DDP resistance. Exp Oncol 2007; 29: 197–202.

Bhattacharya R, Ye X-C, Wang R, et al. Intracrine VEGF signaling mediates the activity of prosurvival pathways in human colorectal cancer cells. Cancer Res 2016; 76: 3014–24.

Chen B, Le W, Wang Y et al. Targeting negative surface charges of cancer cells by multifunctional nanoprobes. Theranostics 2016; 6: 1887–98.

Kim H, Ishibashi K, Okada T, Nakamura C. Adhesion strengths between cancer cells with different malignancies and endothelial cells measured using atomic force microscopy. Jpn J Appl Phys 2019;59: SDDE01. .

Buchheit CL, Weigel KJ, Schafer ZT. Cancer cell survival during detachment from the ECM: multiple barriers to tumour progression. Nature Rev Cancer 2014; 14: 632-41

Peppicelli S, Ruzzolini J, Bianchini F, et al.Anoikis resistance as a further trait of acidic-adapted melanoma cells. J Oncol 2019; 2019: 8340926.

Gupta P, Gupta N, Fofaria NM, et al. HER2-mediated GLI2 stabilization promotes anoikisresistance and metastasis of breast cancer cells. Cancer Lett 2019; 442: 68–81.




How to Cite

Pyaskovskaya, O., Kolesnik, D., Garmanchouk, L., Yanish, Y., & Solyanik, G. (2023). Role of tumor/endothelial cell interactions in tumor growth and metastasis. Experimental Oncology, 43(2), 104–110.



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