What is Metastasis Organotropism?
Organotropism is the affinity for chemicals or microorganisms to target specific tissues or organs. Metastasis organotropism is the tendency for certain metastasized cells to target specific organs. Examples of this can be seen in prostate cancers (which are coupled with bone metastasis), colorectal cancers (which are often paired with liver metastasis) and breast cancers (of which bone, liver and lung metastasis are evident) (1).
Theories and Pathways
Paget's "Seed and Soil" Theory
The seed and soil theory was first proposed by surgeon Stephen Paget in 1889 when he observed 735 breast cancer patients with non-random secondary metastasis of the bones and visceral organs (2). He proposed that certain metastasized tumour cells (which he termed "seeds") would be able to thrive better in certain microenvironments and thus preferred specific organs (these microenvironments he termed "soil") (2). When the correct "seed" met the correct "soil" then tumours would form (2).
Integrating Paget and Ewing’s Theories
Paget's "seed and soil" theory was challenged by pathologist James Ewing in 1928 who proposed the pattern of metastasis organotropism seen in cancer as a result of the anatomical structure of the vascular system (2). By this theory, primary metastasized tumours would travel to organs that receive a large amount of blood (and thus have a vast circulatory network) or organs that are immediately downstream of it (2). Though a prominent theory for decades, this could not explain the non-random observation of organs that receive little blood from the vascular system (like the bone and adrenals) being commonly coupled with certain cancers while organs that play important roles in the circulatory system (like the heart and kidney) being seen sporadically in cancers (2).
In 1979, Dr. Everett D. Sugarbaker suggested that involvement of other anatomical systems (like the lymph system or the efferent venous circulation systems) along with the vascular system could be the cause of common regional secondary metastasis organotropism while targeted distant secondary metastasis organotropism could be due to other mechanisms (2). A 1976 paper by Peter Nowell proposed that cancer tumours undergo clonal evolution, giving rise to heterogeneous tumour cells (6). In 2012 a new hypothesis was suggested integrating Paget and Ewing’s two theories (3). When looking at patients that carry late stage primary cancers, tumour cells (called circulating tumour cells (CTCs)) can be found within the vascular system of the body (3). This suggests that the “seeds” in Paget’s theory are “flowing” within the vascular system and can at any time metastasis in an organ that posses the correct “soil” (microenvironment) (3). Since the CTCs are heterogeneous in nature, a “seed” can flow into organs and not metastasize (due to the microenvironment being unable to support it) and this may continue to occur until a CTC has obtained the necessary mutations to survive within a niche (3).
The Cancer Stem Cells, metastasis and the pre-metastatic niche
Cancer stem cells (CSCs) are a small population of tumour initiating cells found within heterogeneous tumour cells (4). CSCs are immortal cells cable of self-proliferation, differentiation into multiple tumour types and avoiding current cytotoxic cancer therapies (4). First found in acute myeloid leukemia cells after transplantation in mice, these CSCs have begun to surface in several cancers with solid tumours as well (brain, colon, liver, lung, pancreatic and breast to name a few) (4, 5). As with normal stem cells, CSCs are hypothesized to also require specialized niches to support and maintain their “stemness” (4). Due to these traits, CSCs are suspected of playing important roles in cancer metastasis (4). [Refer to Chapter 5]
Though much of the metastatic pathways of CSCs are unknown, many theories have been proposed (2). Two similar theories suggest that metastasis CSCs involvement using a combination of Paget’s and Ewing’s theories (2). The CSCs would play the role of the “seed” while a suitable organ would be the “soil” (2). If CSCs within the primary tumour already possess the optimal mutations for survival within a specific organ, it will travel through body, depositing to other niches but not flourishing (due to the wrong type of microenvironmental support) until it reaches the correct “soil” (2). The second theory suggests the CSCs have not required the proper mutations for survival within a specific organ, but acquire those mutations after being deposited within a niche (2).
A third theory on the metastatic properties of CSCs is known as the pre-metastasis niche model (2). A paper published by Kaplan et al. in 2005 first described seeing lung and melanoma carcinomas secreting placental and vascular endothelial growth factors (now termed pre-metastasis niche factors) to initiate expression of vascular endothelial growth factor receptor 1 (VEGFR1) by haematopoietic progenitor cells (found in the bone marrow) prior to tumour cell arrival into secondary organs (7). Expression of VEGFR1 by haematopoietic progenitor cells caused the formation of fibronectin-rich patches within target organs setting up an ideal niche for tumour arrival (7). This suggests that primary malignant tumours play a role in preparing the ideal niche for metastasis through signaling prior to the arrival of the tumour cells into the secondary niche (7).
Examples of Organotropism
Though a rare type of ovarian cancers, the Krukenberg tumour is one of the most well known tumours amongst physicians (8). In 1896, a physician by the name of Friedrich Ernst Krukenberg published an article of what he believed was a new type of primary ovarian tumour (8). It would be later determined that the Krukenberg tumour observed was actually a metastasized tumour that originated from gastrointestinal primary tumours (8). The stomach is the most common primary tumour sight for Krukenberg tumours (making up 70% of the cases), displaying a preference for metastasis to the ovaries (9). It has been found that adenocarcinomas made of signet ring cells are commonly found ovary metastasis, the most common of these being the infiltrative gastric adenocarcinoma (9).
The lung, liver, bone and lymph nodes are areas of the body that are often targeted by primary breast cancer tumours (2, 10). It has been noted that breast cancer metastasis and migration resembles normal leukocyte trafficking, which are regulated by chemokines and chemokine receptors (10). Two of these receptors (CXCR4 and CCR7) were found by Muller et al. to be highly expressed in breast cancer tumour cells (10). Further research into the metastatic targeting of secondary organs found that the ligands of CXCR4 and CCR7 (CXCL12/SDF-1α and CCL21/6Ckine respectively) were found highest in organs targeted by breast cancer tumour cells (10). This shows that chemokines may play a critical role in breast cancer (or other cancers) in determining the destination of primary tumour cells (10).
(1) Lu X., and Kang Y. 2007. Organotroposim of Breast Cancer Metastasis. J Mammary Gland Biol Neo 12:153-162. doi 10.1007/s10911-007-9047-3.
(2) Ribatti, D. 2010. Protagonists of Medicine. Springer.
(3) Scott J., Kuhn P., and Anderson ARA. 2012. Unifying metastasis - integrating intravasation, circulation and end organ colonization. Nat Rev Can. doi:10.1038/nrc3287.
(4) Fabian A., Vereb G., and Szollosi J. 2013. The hitchhiker’s guide to cancer stem cell theory: markers, pathways and therapy. Int Soc Adc Cyto 83A:62-71. doi:10.1002/cyto.a.22206.
(5) Li F., Tiede B., Massague J., and Kang Y. 2007. Beyond tumorigenesis: cancer stem cells in metastasis. Cell Res 17:3-14.
(6) Marte B. 2013. Tumour heterogeneity. Nature 501:327. doi: 10.1038/501327a.
(7) Kaplan RN., Riba RD., Zacharoulis S., Bramley AH., Vincent L., Costa C., MacDonald DD., Jin DK., Shido K., Kerns SA., Zhu Z., Hicklin D., Wu Y., Port JL., Altorki N., P ER., Ruggero D., Shmelkov SV., Jensen KK., Rafii S. and Lyden D. 2005. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature 438:820-827. doi:10.1038/nature04186.
(8) Young RH. 2006. From Krukenberg to Today: The Ever Present Problems Posed by Metastatic Tumors in the Ovary: Part I. Historical Perspective, General Principles, Mucinous Tumors Including the Krukenberg Tumor. Adv Anat Pathol 13(5):205-227. doi: 10.1097/01.pap.0000213038.85704.e4
(9) Al-Agha OM. and Nicastri AD. 2006. An in-depth look at Krukenberg tumour. Arch Pathol Lab Med 130:1725-1730.
(10) Muller A., Homey B., Soto H., Ge N., Catron D., Buchanan ME., McClanahan T., Murphy E., Yuan W., Wagner SN., Barrera JL., Mohar L., Verastegui E. and Zlotnik A. 2001. Involvement of chemokine receptors in breast cancer metastasis. Nature 410:50-56.