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Paget’s “Seed and Soil” Theory of Cancer Metastasis

An Idea Whose Time has Come

Akhtar, Mohammed, MD, FCAP, FRCPath, FRCPA*; Haider, Abdulrazzaq, MD*; Rashid, Sameera, MD; Al-Nabet, Ajayeb Dakhilalla M.H., PhD*

Advances in Anatomic Pathology: January 2019 - Volume 26 - Issue 1 - p 69–74
doi: 10.1097/PAP.0000000000000219
Review Article

The concept that the pattern of metastatic spread of cancer is not random and that cancer cells exhibit preferences when metastasizing to organs, dates back to 1889 when Steven Paget published his “seed and soil” hypothesis. He proposed that the spread of tumor cells is governed by interaction and cooperation between the cancer cells (seed) and the host organ (soil). Extensive studies during the last several decades have provided a better understanding of the process of metastatic spread of cancer and several stages such as intravasation, extravasation, tumor latency, and development of micrometastasis and macrometastasis have been defined. Furthermore, recent studies have shown that the target organs may be prepared for metastatic deposits by the development of premetastatic niches. This specialized microenvironment is involved in promoting tumor cell homing, colonization, and subsequent growth at the target organ. The premetastatic niche consists of accumulation of aberrant immune cells and extracellular matrix proteins in target organs. The primary tumor plays a key role in the development of premetastatic niches by producing tumor-derived soluble factors which mobilize bone marrow-derived hematopoietic cells to the premetastatic niche. Exosomes-derived from the primary tumor also contribute to cancer-favorable microenvironment in the premetastatic niches. These changes prime the initially healthy organ microenvironment and render it amenable for subsequent metastatic cell colonization.

*Department of Laboratory Medicine and Pathology, Division of Anatomic Pathology

Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, Doha, Qatar

The authors have no funding or conflicts of interest to disclose.

Reprints: Mohammed Akhtar MD, FACP, FRCPath, FRCPA, Department of Laboratory Medicine and Pathology, Hamad Medical Corporation, P.O. Box 3050, Doha, Qatar (e-mail: dr.mohammed.akhtar@gmail.com).

All figures can be viewed online in color at www.anatomicpathology.com.

Cancer metastasis is the spread of cancer cells beyond where the tumor originated to other parts of the body with the formation of new tumors. It is the single event that results in the death of most patients with cancer. At the time of cancer diagnosis, at least half of the patients already present clinically detectable metastatic disease. Although the primary tumor, in most cases may be eradicated by therapeutic modalities such as surgical resection, radiotherapy, and chemotherapy, its metastases, when distributed at distant sites in the body, are most difficult to eradicate by any of the currently available therapeutic means, and finally, cause the patient’s death. Thus, metastasis is the most life-threatening event in patients with cancer.1–3

It has long been observed that most cancers show an organ-specific pattern of metastases. For example, colon carcinomas metastasize usually to liver and lung but rarely to bone, skin, brain, and kidneys. In contrast, breast carcinomas, frequently form metastases in most of these organs. Similarly, prostate cancer metastasizes to the bone and only rarely to lung and liver. Whether the distribution of metastatic disease is a random process determined by the patterns of blood supply and lymphatic flow or due to the active interaction between the tumor cells and the host organ has long been a matter of debate.2–4

The purpose of this review is to provide a brief perspective on our understanding of the mechanisms of metastasis and to provide an update on recent findings with regard to the interactions between the cancer cells and host organ harboring the metastasis and to highlight changes in the microenvironment of these organs before and after the arrival of the metastatic cancer cells.

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SEED AND THE SOIL THEORY

Steven Paget (son of the famous English surgeon and pathologist Sir James Paget) proposed the “seed and soil” theory of metastasis, which was based on analysis of 735 fatal cases of breast cancer, complete with the autopsy, as well as many other cancer cases from the literature. His findings were published in Lancet in 1889. He argued that the distribution of metastases cannot be due to chance: the “seed” refers to certain tumor cells with metastatic potential, and the “soil” is any organ or tissue providing a proper environment for the growth of the seeds. Paget suggested that the spread of metastatic cells was organ specific and not merely anatomic and involved interaction between the cancer cells and the host organ. He concluded that metastases developed only when the seed and soil were compatible.5 This concept was in opposition to the prevailing mechanistic hypothesis of Rudolf Virchow who considered metastasis as the arrest of tumor cell emboli in the vasculature.2,6

In 1928, James Ewing7 challenged Paget’s “seed and soil” theory and hypothesized that metastatic dissemination occurs by purely mechanical factors that are a result of the anatomic structure of the vascular system. Thus, it would be completely accounted for by the vascular connections of the primary tumor so that tumor cell emboli are much more likely to be mechanically trapped in the circulatory network of the first connected organ, which will then sustain the highest burden of metastatic colonization.

Other organs receive less tumor cells and develop fewer metastatic tumors. That became the dominant view point and for the next several decades the concept of “seed and soil” languished in the shadows. This proposal, however, does not explain the observation that some organs, such as brain, bone, and adrenals, are served by a small fraction of the circulatory volume, yet they are frequently involved by metastatic deposits of certain cancers. In contrast, organs, such as heart, muscle, skin, kidney, and spleen, each of which receives a considerable supply of blood, only occasionally develop metastatic disease.3

In 1979, Sugarbaker8 postulated that while the regional metastases could be due to anatomic or mechanical issues such as lymphatic drainage as stated by Ewing, metastases to distant organs are site specific and require a different explanation. Seminal work by Hart and Fidler in the 1980s supported Paget’s “seed and soil” theory by showing preferential homing of tumor cells of B16 melanoma in specific distant sites. Their work conclusively demonstrated that while potentially metastatic tumor cells reached the vasculature of all organs, the development of metastases occurred selectively in certain organs but not others.9

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THE START OF THE METASTATIC JOURNEY

The process of metastasis starts with the release of malignant cells from its adhesive attachments to other cells and the extracellular matrix including the basement membranes. Further, the cancer cells acquire mesenchymal-like properties via a process called epithelial mesenchymal transition. This is mediated by cadherin molecule switching involving downregulation of E-cadherin and upregulation of mesenchymal cadherins such as N-cadherin, integrin-αvβ6, vimentin, and matrix metalloproteinase.9 Such cells assume motile phenotype and acquire migratory capabilities and can interact with components of the extracellular matrix and contribute to it by synthesizing and organizing new components. They also remodel the extracellular matrix through the production of matrix-degrading metalloproteinases. Thus, the loss of cell-cell adhesions allows malignant tumor cells to dissociate from the primary tumor and changes in cell-matrix interaction enable the cells to invade the surrounding stroma. As these motile cells pass through the basement membrane and extracellular matrix, some tumor cells will penetrate the blood vessels, thus entering the circulation (intravasation) (Fig. 1). Tumor cells that have successfully invaded the blood vessels adhere to blood platelets that protect them from destructive physical forces such as hemodynamic shear and from sensitized killer mononuclear cells. At the same time, there is an activation of thrombosis with fibrin deposition. The aggregation of platelets, fibrin, and tumor cells creates a tumor-platelet complex that essentially acts as an embolus (Fig. 2). From this point, these tumor cells move away from the primary site and circulate in the blood circulation where they would encounter resistance by the immune system and the mechanical stresses of blood flow. Some tumor cells will eventually survive and adopt a process to leave the blood circulation, known as extravasation which is the reverse of intravasation and in which cells adhere and penetrate the blood vessel wall again. The tumor cells that escape from the circulation, invade the host tissues.10–13 These cells undergo mesenchymal-epithelial transformation and are now designated as disseminated tumor cells (DTCs) (Fig. 3).

FIGURE 1

FIGURE 1

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

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HOMING OF CIRCULATING TUMOR CELLS

Various explanations have been proposed for the site selectivity and organ tropism of blood-borne distant metastases, including tumor cell surface characteristics, adhesion between tumor cells and the target organ components and response to specific host tissue growth factors and chemokines. An explanation for the different sites of tumor growth involves interactions between the metastatic cells and the organ environment, possibly in terms of specific binding to endothelial cells. Endothelial cells in the vasculature of different organs express different cell surface receptors and growth factors that influence the phenotype of the corresponding metastases. Greene and Harvey first suggested that the organ distribution patterns of metastatic foci were dependent on the formation of sufficient adhesive bonds between arrested tumor cells and endothelial cells, and they hypothesized that these interactions were similar to those of lymphocyte/endothelial cells at sites of inflammation.14–16

Circulating immune and stem cells are known to use chemokine-mediated signaling to home on specific organs. Chemokines are growth factor–like molecules that bind to G-coupled receptors. They induce leukocytes to adhere tightly to endothelial cells and to migrate towards a gradient. Tumor cells also use similar mechanisms to direct metastatic organ preference. The best-known example is the expression of chemokine receptor 4 (CXCR4) in breast cancer. Tumors with CXCR4 expression migrate to organs that express high levels of its ligand CXCL12. CXCL12 is expressed in the common sites of metastasis for breast cancer: lung, liver, bone marrow, and brain. Similarly, melanoma cells may be attracted to certain organs using CCL27/CCR10 chemokine receptor combination.16,17

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TUMOR LATENCY

The fact that tumor cells arrive and establish residence at a new and potentially hostile environment does not mean that they will necessarily survive and proliferate in the new location. Survival and subsequent proliferation, however, is a prerequisite for development of a secondary tumor at the new location. Only a small fraction of these cells ultimately survives in the new tissue location. It has been estimated that <0.01% of circulating tumor cells eventually succeed in forming secondary growths.18

After extravasation, a common theme of the metastatic process is settlement of DTCs into latency, which can last from several weeks to decades (Fig. 4). In cellular latency isolated tumor cells enter a state of proliferative quiescence. Indeed, in patient bone marrow samples most DTCs are found as quiescent single cells. Another form of tumor latency is the establishment of micrometastasis (Fig. 5). This is metastatic lesion where tumor cells form small aggregates in which rate of proliferation and tumor cell attrition are exactly balanced. The loss of tumor cells may be due to apoptosis, insufficient vascularization, or to constant culling by immune defenses. Consequently, in a micrometastasis despite active tumor cell proliferation, the tumor size remains too small for clinical detection by conventional methods.19–21

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

The duration of metastatic latency varies between cancer types, and for the most aggressive ones it is very short, resulting in high relapse and mortality rates following diagnosis. In lung cancer, the metastatic latency interval usually lasts only a few weeks. In this type of cancer, malignant cells acquire metastatic traits for rapid and massive cell dissemination, followed by colonization of multiple secondary organs. The short latency in lung cancer implies that malignant cells in the primary tumor acquire most of the metastatic traits, thus enabling them to overtake organs immediately after arrival. In contrast, a well-known example of a tumor type with very long latency is prostate cancer. Similarly, some of the breast cancer metastasis may also remain dormant only to present with widespread metastasis years and even decades later.22

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THE METASTATIC NICHE AND FORMATION OF MACROMETASTASIS

DTCs need time to alter or unleash the required functions for tumor initiation and expansion in the secondary site. For the successful establishment of a metastasis several crucial events must take place, the most important among which are cell cycle activity and angiogenesis. It is obvious then that there are intrinsic differences in genomic makeup of tumor cells that must be evaluated to understand the factors intrinsic to the cell (seed). However, it is equally important to acknowledge the microenvironmental condition of the host tissue, the soil that plays a key role in the acquisition of proliferative phenotype by the tumor cells.

Studies using, radioactive labeling of the injected cancer cells showed that they were equally likely to be trapped in a variety of tissue.18 So, just landing in a tissue is not enough for cancer cells to develop a secondary tumor; rather, some role of the tissue itself may be crucial in sustaining the new growth. The findings of Tarin et al23 that the development of secondary cancer was rare even upon direct deposition of millions of tumor cells into the vena cava (to reduce ascites from ovarian cancer) is a good indication of the importance of other factors involved.

In stem cell biology the specialized microenvironment that supports stem cell maintenance and actively regulates cell function and proliferation is termed as niche.24 A similar model has been suggested to delineate the interactions of malignant cells with their microenvironment at metastatic sites. This microenvironment comprises supportive non-neoplastic stromal cells, soluble factors, vascular networks, nutrients and metabolic components, and the structural extracellular matrix architecture. Although the precise genetic makeup of a cell is undoubtedly pivotal in determining its malignant phenotype, the metastatic niche model stipulates that microenvironmental factors are also important in permitting malignant cells to realize their metastatic potential. Thus, with the right genetic makeup of the tumor cells accompanied by a permissive and supportive environment in the host organ, the tumor cells may proliferate and ultimately develop into a clinically detectable macrometastasis. The metastatic niche model suggests that a suitably conducive microenvironment must evolve for tumor cells to be able to engraft and proliferate at secondary sites with the transition from micrometastatic to macrometastatic status.25 The idea that cancer cells require some nourishment and support from their environment to develop is an important focus of research today, with the aim of unraveling the molecular mechanisms that bring seed and soil together to promote metastasis.

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THE CONCEPT OF PREMETASTATIC NICHE

The premetastatic niche can be defined as a supportive and receptive tissue microenvironment undergoing a series of molecular and cellular changes to form the metastatic-designated sites, prior to the arrival of the metastatic tumor. Dr Lyden and colleagues pioneered the research on the premetastatic niche and the role and significance of the premetastatic niche in metastasis has attracted more and more attention in recent years.26 Their landmark study was the first demonstration of a microenvironment designed to attract tumor cells to a target organ and set the stage for future work to discover additional factors that contribute to premetastatic niche formation.

The process of premetastatic niche formation in distant organs is initiated by the primary tumor that produces tumor-derived secreted factors prior to tumor dissemination.27 These factors include vascular endothelial growth factor (VEGF-A) and placental growth factor among others. These factors increase the proliferation of fibroblast-like stromal cells, which contribute to local deposition of fibronectin. Tumor-derived secreted factors promote premetastatic niche formation by mobilizing and recruiting VEGFR1+ bonemarrow-derived hematopoietic progenitor cells directly from the bone marrow to the premetastatic niche (Fig. 6). These cells express VLA−4 that binds to fibronectin and allows them to assemble at the site. Most notably, the VEGFR1+ niche cells act as harbingers of organ-specific carcinoma spread. Others, such as tumor necrosis factor alpha (TNF-a) and transforming growth factor b (TGF-b), along with VEGF-A, induce the expression of S100A8 and S100A9 in the lung to develop premetastatic niches.25–30

FIGURE 6

FIGURE 6

Premetastatic niche formation is facilitated in large part by the presence of a suppressed immune system. Primary tumors recruit myeloid cells, which are the precursors to immune cells. These cells enable the tumor cells to avoid detection by the immune system as they metastasize, and thus allow the metastasis to flourish. Once the primary tumors have entered the bloodstream, myeloid cells that have been recruited by the tumor protect the cancer cells from detection by the immune system, which would otherwise be more likely to be effective in halting metastasis. Myeloid progenitor cells, recruited at various stages in their cell cycle, are believed to constitute much of the premetastatic niche, as they can protect the tumor cells from the standard immune response as the cancer cells attempt to colonize the premetastatic niche. Given their important role in protecting the growing metastasis from immune system attacks, myeloid cells are a key factor in the development of the premetastatic niche, and thus eventually in promoting metastases.29,31

Chemokines, also play a significant role in the creation of premetastatic niches and metastases. The primary tumor, to evade detection by the immune system, uses chemokines to increase recruitment of bone marrow-derived myeloid cells to secondary organs. In addition, cancer cells from the primary tumor can be used to induce inflammation in the future site of the premetastatic niche in the secondary organ, which is like the immune response created by an infection. Thus, the large presence of immune cells allows the premetastatic niche to ward off attacks by the immune system and therefore allow the tumor to metastasize without inhibition.29,32

The formation of a premetastatic niche not only involves the recruitment of foreign cells, such as immune cells, but also the reprogramming of the resident stromal cells to facilitate metastatic growth. Normal lung fibroblasts express miR-30 family members to restrain MMPs, such as MMP9, to stabilize the lung vasculature. Cancer cells reprogram fibroblasts to decrease their expression of miR-30 family members, resulting in enhanced MMP activity, vascular permeability, and metastasis. Factors secreted from the primary tumor induce the expression of α-smooth muscle actin—in premetastatic fibroblasts, activating them to induce remodeling extracellular matrix through secretion of fibronectin, Lysyl Oxidases LOX and LOXL2, thereby generating a more permissive microenvironment for survival and outgrowth of DTC.28,29,33–35

Thus, immune suppression, combined with hypoxia and changes in extracellular matrix, among other processes, are essential steps in creating premetastatic niches that allow tumor cells to grow in a foreign and hostile environment without being destroyed by the typical response of the immune system.

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ROLE OF EXOSOMES IN TUMOR METASTASIS

Exosomes are spherical to cup shaped, lipid bilayer membrane nanovesicles 40 to 100 nm in diameter. These vesicles are secreted by many cells and can be found in most body fluids such as urine and blood as well as in supernatants of cultured cells. Exosomes must be differentiated from other secreted cellular entities such as microvesicles (50 to 1000 nm in diameter) and ectosomes, which are microvesicles derived from neutrophils or monocytes and apoptotic bodies (500 to 2000 nm in diameter).36,37

Exosome formation is a fine-tuned process which includes 4 stages: initiation, endocytosis, multivesicular bodies formation, and exosome secretion. Multivesicular bodies are endocytic structures formed by the budding of an endosomal membrane into the lumen of the compartment (Fig. 7). After vesicular accumulation, the multivesicular bodies are either sorted for cargo degradation in the lysosome or released into the extracellular space as exosomes by fusing with the plasma membrane.38

FIGURE 7

FIGURE 7

In addition to lipids, nucleic acids, and proteins have also been detected in exosomes. The protein composition of tumor cell-derived exosomes has been well characterized for several cancers by using different proteomic methods. To date, 4563 proteins, 1639 mRNAs, and 764 miRNAs have been identified in exosomes from different species and tissues by independent examinations.39

The exosomes can transfer their constituentsand cargo to neighboring or distant cells with preservation of their function. Several mechanisms for the uptake of exosomes by recipient cells, such as exosome fusion with the membrane of the recipient cell, endocytosis by phagocytosis, and receptor-ligand interaction.40 Initially discovered as the garbage bags for removal of unwanted material from cells, the role of exosomes in immune response and cancer is gradually recognized. Exosomes are now considered important mediators in intercellular communication. The capability of exosomes to transfer proteins, DNA, mRNA, as well as non-coding RNAs has made them an attractive focus of research into the pathogenesis of different diseases, including cancer.40,41

It has been noted that cancer cells secrete much higher amounts of exosomes in comparison with nontransformed cells. These exosomes not only influence proximal tumor cells and stromal cells in local microenvironment, but also can exert systemic effects when participating in blood circulation. Exosomes have been shown to be implicated in the induction of apoptosis of cytotoxic T cells, expansion and function of regulatory T cells (Treg cells), induction of M2 polarization of macrophages, inhibition of cytotoxicity of natural killer cells, inhibition of differentiation of dendritic cells, expansion and activation of myeloid-derived suppressor cells and mobilization of neutrophils. Exosomes released under hypoxic conditions can stimulate angiogenesis through interactions with endothelial cells.

Exosomal transforming growth factor β (TGFβ) can induce differentiation of fibroblasts into tumor-supporting myofibroblasts and exosomes from ovarian cancer are able to convert adipose-derived mesenchymal stem cells into myofibroblast-like cells, supporting tumor growth and angiogenesis.36,41

As exosomes can transfer specific proteins and nucleic acids to recipient cells in the tumor microenvironment or at specific distant sites, cancers have used exosomes as a tool by which cancer cells can transfer malignant phenotype to normal cells and establish a fertile local and distant microenvironment to help cancer cell growth. Exosomes contribute to tumor metastasis by enhancing tumor cell migration and invasion, remodeling the extracellular matrix and establishing premetastatic niche.36,41–43

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CONCLUSIONS

A better understanding of the mechanisms of metastatic disease in recent years seems to support the seed and soil theory proposed by Steven Pagets almost 130 years ago. Preventing metastasis in high-risk patients would be far better than having to treat it later. Recent recognition of the concept of the premetastatic niche allows researchers to consider several new possibilities for treating cancer.44 Research on the mechanisms that control and support the viability of latent metastatic cells should yield clues for targeting cancer with the goal of preventing metastasis. Factors from the primary tumor that structurally alter the secondary organ to facilitate its colonization by tumor cells could also potentially be targeted to stop metastasis. Recognition of the role of exosomes in tumor progression is also an important potential target for early detection of cancer and prevention of premetastatic niche formation.

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REFERENCES

1. Liotta LA, Stetler-Stevenson WG. Principles of Molecular Cell Biology of Cancer: Cancer Metastasis, 4th ed. Philadelphia, PA: JB Lippincott Co; 1993.
2. Chambers AF, Groom AC, Mac Donald IC. Dissemination and growth of cancer cells in metastatic sites. Nat Rev Cancer. 2002;2:563–572.
3. Ribatti D, Mangialardi G, Vacca A. Stephen Paget and the ‘seed and soil’ theory of metastatic dissemination. Clin Exp Med. 2006;6:145–149.
4. Nguyen DX, Bos PD, Massagué J. Metastasis: from dissemination to organ specific colonization. Nat Rev Cancer. 2009;9:274–284.
5. Paget S. The distribution of secondary growths in cancer of the breast. Lancet. 1889;133:571–573.
6. Pachmayr E, Treese C, Stein U. Underlying mechanisms for distant metastasis —molecular biology. Visc Med. 2017;33:11–20.
7. Ewing J. ed. Neoplastic Diseases: a Treatise on Tumours Metastasis, 3rd ed. Philadelphia: Saunders; 1928:76–88.
8. Sugarbaker EV. Cancer metastasis: a product of tumor host interactions. Curr Probl Cancer. 1979;3:1–59.
9. Hart IR, Fidler IJ. Role of organ selectivity in the determination of metastatic patterns of B16 melanoma. Cancer Res. 1980;40:2281–2287.
10. Nguyen DX, Bos PD, Massague J. Metastasis: from dissemination to organ-specific colonization. Nat Rev Cancer. 2009;9:274–284.
11. Martin TA, Ye L, Sanders AJ, et alJandial Rahul. Cancer invasion and metastasis: molecular and cellular perspective. Metastatic Cancer: Clinical and Biological Perspectives. Austin, TX: Landes Bioscience; 2013.
12. Kent W, Hunter KW, Crawford NPS, et al. Mechanisms of metastasis. Breast Cancer Res. 2008;10(suppl 1):S2 1–S2 10.
13. Munguti J, Sammy M. Mechanisms of tumor metastasis: anatomical mimicry? OA Anatomy. 2013;1:23.
14. Bogenrieder T, Herlyn M. Axis of evil: molecular mechanisms of cancer metastasis. Oncogene. 2003;22:6524–6536.
15. Greene HS, Harvey EK. The relationship between the dissemination of tumor cells and the distribution of metastases. Cancer Res. 1964;24:799–811.
16. Sarvaiya PJ, Guo D, Ulasov I, et al. Chemokines in tumor progression and metastasis. Oncotarget. 2013;4:2171–2185.
17. Mukherjee D, Zhao J. The role of chemokine receptor CXCR4 in breast cancer metastasis. Am J Cancer Res. 2013;3:46–57.
18. Fidler IJ. Metastasis: quantitative analysis of distribution and fate of tumor emboli labeled with 125 I-5-iodo-2′-deoxyuridine. J Natl Cancer Inst. 1970;45:773–782.
19. Pollard JW. Defining metastatic cell latency. N Engl J Med. 2016;375:280–282.
20. Massagué J, Obenauf JA AC. Metastatic colonization. Nature. 2016;529:298–306.
21. Lambert WA, Pattabiraman DR, Weinberg RA. Emerging biological principles of metastasis. Cell. 2017;168:4670–4691.
22. Gomis RR, Gawrzak S. Tumor cell dormancy. Mol Oncol. 2017;11:62–78.
23. Tarin D, Price J, Kettlewell M, et al. Mechanisms of human tumor metastasis studied in patients with peritoneovenous shunts. Cancer Res. 1984;44:3584–3592.
24. Morrison SJ, Spradling AC. Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell. 2008;132:598–611.
25. Psaila B, Lyden D. The metastatic niche: adapting the foreign soil. Nat Rev Cancer. 2009;9:285–293.
26. Kaplan RN, Riba RD, Zacharoulis S, et al. VEGFR1-positive haematopoietic bone marrow progenitors initiate the pre-metastatic niche. Nature. 2005;438:820–827.
27. Peinado H, Lavotshkin S, Lyden D. The secreted factors responsible for pre-metastatic niche formation: old sayings and new thoughts. Semin Cancer Biol. 2011;21:139–146.
28. Chin AR, Wang SE. Cancer tills the premetastatic field: mechanistic basis and clinical implications. Clin Cancer Res. 2016;22:3725–3733.
29. Peinado H, Zhang H, Matei IR, et al. Pre-metastatic niches: organ-specific homes for metastases. Nat Rev Cancer. 2017;17:302–317.
30. Liu Y, Cao X. Characteristics and significance of the premetastatic niche. Cancer Cell. 2016;30:668–681.
31. Kitamura T, Qian B-Z, Pollard JW. Immune cell promotion of metastasis. Nat Rev Immunol. 2015;15:73–86.
32. Law AMK, Lim E, Ormandy CJ, et al. The innate and adaptive infiltrating immune systems as targets for breast cancer immunotherapy. Endocr Relat Cancer. 2017;24:R123–R144.
33. Aguado BA, Bushnell GG, Rao SS, et al. Engineering the pre-metastatic niche. Nat Biomed Eng. 2017;1:1–28.
34. Cox TR, Bird D, Baker A-M, et al. LOX-mediated collagen crosslinking is responsible for fibrosis-enhanced metastasis. Cancer Res. 2013;73:1721–1732.
35. Lu P, Weaver VM, Werb Z. The extracellular matrix: a dynamic niche in cancer progression. J Cell Boil. 2012;196:395–406.
36. Weidle HU, Birzele F, Kollmorgen G, et al. The multiple roles of exosomes in metastasis. Cancer Genomics Proteomics. 2017;14:1–16.
37. Thery C, Zitvogel L, Amigorena S. Exosomes: composition, biogenesis and function. Nat Rev Immunol. 2002;2:569–579.
38. Li W, Li C, Zhou T, et al. Role of exosomal proteins in cancer diagnosis. Mol Cancer. 2017;16:145.
39. Zhang X, Yuan X, Shi H, et al. Exosomes in cancer: small particle, big player. J Hematol Oncol. 2015;8:83.
40. Mulcahy LA, Pink RC, Carter DRF. Routes and mechanisms of extracellular vesicle uptake. J Extracell Vesicles. 2014;3:10.
41. Rashed MH, Bayraktar E, Helal GK, et al. Exosomes: from garbage bins to promising therapeutic targets. Int J Mol Sci. 2017;18:538.
42. Young Hwa Soung YH, Nguyen T, Cao H, et al. Emerging roles of exosomes in cancer invasion and metastasis. BMB Rep. 2016;49:18–25.
43. Jia Y, Chen Y, Wang Q, et al. Exosome: emerging biomarker in breast cancer. Oncotarget. 2017;8:41717–41733.
44. Zoccoli A, Iuliani M, Pantano F, et al. Premetastatic niche: ready for new therapeutic interventions? Exp Opin Ther Targets. 2012;16(suppl 2):S119–S129.
Keywords:

seed; soil; metastasis; exosomes; niche; premetastatic; macrophage; intravasation; extravasation; bone marrow

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