‘Catch me if you can’ – Vascular mimicry and cancer metastasis

A well-studied process employed by the cancer machinery to provide oxygen and nutrients to the growing tumor mass is called ‘angiogenesis’; leading to the formation of new blood vessels and vasculature inside the tumor to nourish and sustain its rapid growth. Initially, it was thought that this process was due to the extension of existing blood vessels in the vicinity of the tumor by secretion of vascular endothelial growth factors such as VEGF, overexpressed by these cancer cells. However, a recent phenomenon was identified in cancers called ‘vascular mimicry’ wherein tumors can impersonate endothelial cells that line normal blood vessels forming vasculature-like networks resembling blood vessels within the tumor.

Figure showing tumor-derived network due to vascular mimicry. Courtesy: Ref. 2

Hendrix and his colleagues first identified this phenomenon in human melanoma cells in 1999 (1, 2). These tumor-cell-lined, matrix-rich networks then connected with normal blood vessels allowing cancer cells to enter the blood circulation and disseminate to distant organs (3). Like many radical ideas in science, the idea of vascular mimicry too faces a lot of opposition since its initial discovery. However, a lot of research since then has strengthened the findings and furnished additional evidence to confirm its existence. In addition, the failure of several anti-angiogenic drugs such as Bevacizumab (also called by its tradename Avastin), to significantly improve patient survival has fuelled doubts if vascular mimicry could be behind it. To make matters worse, the cells which exhibit vascular mimicry were found to be chemo-resistant and have stem-cell-like features enabling them to differentiate into different cell types (4). These cancer cells were dubbed ‘smart cells’, as they successfully mimic blood vessels, escape into circulation, evade drugs, survive immune surveillance, metastasize to distant organs and re-establish new colonies.

Two proteins that have recently been implicated in this process and found to be overexpressed in breast and lung metastasis, namely, Serpine2 and Slpi; were adequate enough to program the cells to perform vascular mimicry (5). Interestingly, these proteins were found to not only ensure that the primary tumors are fed by the vasculature but also drive metastasis by acting as anticoagulants. Considering this, future research on endothelium-specific markers for anti-vascular therapy must take into account these evasion tactics by tumor cells to be more effective.

References:

1. Kirschmann, D. A., Seftor, E. A., Hardy, K. M., Seftor, R. E., and Hendrix, M. J. (2012) Molecular pathways: vasculogenic mimicry in tumor cells: diagnostic and therapeutic implications, Clin Cancer Res 18, 2726-2732.
2. Hendrix, M. J., Seftor, E. A., Hess, A. R., and Seftor, R. E. (2003) Vasculogenic mimicry and tumor-cell plasticity: lessons from melanoma, Nat Rev Cancer 3, 411-421.
3. Hendrix, M. J. (2015) Cancer: An extravascular route for tumour cells, Nature 520, 300-302.
4. Lezcano, C., Kleffel, S., Lee, N., Larson, A. R., Zhan, Q., DoRosario, A., Wang, L. C., Schatton, T., and Murphy, G. F. (2014) Merkel cell carcinoma expresses vasculogenic mimicry: demonstration in patients and experimental manipulation in xenografts, Lab Invest 94, 1092-1102.
5. Wagenblast, E., Soto, M., Gutierrez-Angel, S., Hartl, C. A., Gable, A. L., Maceli, A. R., Erard, N., Williams, A. M., Kim, S. Y., Dickopf, S., Harrell, J. C., Smith, A. D., Perou, C. M., Wilkinson, J. E., Hannon, G. J., and Knott, S. R. (2015) A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis, Nature 520, 358-362.