‘When a plant goes to seed, the seeds are carried in all directions, but they only grow and live if they fall on congenial soil’- Stephen Paget here, way back in 1889, wasn’t really talking about anything botanical, but was indeed suggesting that there might be a possibility that the disseminated cancer cells (seeds), can only colonize a specific site (soil), if and only if, it provides a congenial environment for it to grow (1).
What decides which site the cancer cells will choose to metastasise?
So, what exactly are we talking about here? We know that as a tumour begins to progress, the cells acquire the ability to launch themselves towards different sites. The cells enter the blood and lymphatic circulation and are practically taken everywhere in the body. The obvious next question you may ask is – what then decides where the tumour cells lodge? Is it entirely the property of the tumour cell? Or can the site by itself play a role in welcoming the cancer cells to successfully colonise there?
Cancer cells have their preferences!
One of the strong contenders of this theory was James Ewing who challenged that metastatic dissemination was mainly a consequence of the dynamics of blood flow. It was only later in 1976 that two scientists, Fidler and Nicolson, showed the first ever evidence of organotropic metastasis (cancer having preferential metastatic sites). They conducted a simple experiment using a labelled metastatic melanoma cell line, that was observed to preferentially metastasise to the lung. They administered the cells into C57BL/6 mice via two routes – IV and intracardiac and observed, that independent of the route, the cells always yielded lung colonies (2). Tumour cells indeed had organ preferences!
What causes these organ preferences?
We now know that the primary tumour itself plays a significant role in preparing its prospective metastatic sites also called the pre-metastatic niche, and this can happen via certain tumour secreted factors and tumour derived Extracellular Vesicles (EVs) (3).
An interesting example of a tumour secreted factor is the enzyme – Lysyl oxidase (LOX). LOX is an enzyme primarily responsible for the crosslinking of collagen fibres. LOX is secreted in excess by the hypoxic tumor cells (cells growing in the reduced oxygen levels), which then enters circulation and accumulates at metastatic sites. A series of interesting experiments conducted using breast cancer cell lines, by the Janine T. Erler group, show how LOX regulates collagen crosslinking creating a fibrotic microenvironment, favouring the persistence and survival of the seeding cancer cells in that region, leading to enhanced outgrowth and metastasis. They further show that therapeutic targeting of LOX abrogates fibrosis as well as metastatic colonization (4).
It would be hence interesting to wonder if we could possibly target the pre-metastatic niche in a way that it may become uncongenial for the circulating tumour cells to colonize. As rightly suggested by Paget:
Although studying the properties of the seed is of importance, observing the properties of the soil may also be useful!
- 1.S. Paget, The distribution of secondary growths in cancer of the breast. 1889. Cancer Metastasis Rev. 8, 98–101 (1989).
- 2.I. Fidler, G. Nicolson, Organ selectivity for implantation survival and growth of B16 melanoma variant tumor lines. J Natl Cancer Inst. 57, 1199–202 (1976).
- 3.H. Peinado, H. Zhang, I. Matei, B. Costa-Silva, A. Hoshino, G. Rodrigues, B. Psaila, R. Kaplan, J. Bromberg, Y. Kang, M. Bissell, T. Cox, A. Giaccia, J. Erler, S. Hiratsuka, C. Ghajar, D. Lyden, Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 17, 302–317 (2017).
- 4.T. Cox, D. Bird, A. Baker, H. Barker, M. Ho, G. Lang, J. Erler, LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 73, 1721–32 (2013).