the cancer diaspora: metastasis beyond the seed...

Perspectives

The Cancer Diaspora: Metastasis beyond the Seed and SoilHypothesis

Kenneth J. Pienta1, Bruce A. Robertson2, Donald S. Coffey1, and Russell S. Taichman3

AbstractDo cancer cells escape the confinement of their original habitat in the primary tumor or are they forced out

by ecologic changes in their homeniche?Describingmetastasis in termsof a simple one-waymigrationof cells

from the primary to the target organs is an insufficient concept to cover the nuances of cancer spread. A

diaspora is the scattering of people away from an established homeland. To date, "diaspora" has been a

uniquely human termused by social scientists; however, the application of the diaspora concept tometastasis

may yield new biologic insights as well as therapeutic paradigms. The diaspora paradigm takes into account,

and models, several variables including: the quality of the primary tumor microenvironment, the fitness of

individual cancer cellmigrants aswell asmigrant populations, the rate ofbidirectionalmigrationof cancer and

host cells between cancer sites, and the quality of the target microenvironments to establish metastatic sites.

Ecologic scientific principles can be applied to the cancer diaspora to develop new therapeutic strategies. For

example, ecologic traps – habitats that lead to the extinction of a species – can be developed to attract cancer

cells to a place where they can be better exposed to treatments or to cells of the immune system for improved

antigen presentation. Merging the social science concept of diaspora with ecologic and population sciences

concepts can inform the cancer field to understand the biology of tumorigenesis and metastasis and inspire

new ideas for therapy. Clin Cancer Res; 19(21); 5849–55. �2013 AACR.

Metastasis Viewed in Terms of MigrationDo cancer cells escape their original habitat in the pri-

mary tumor or are they forced out by ecological changes intheir home niche? The latter process can be considered adiaspora and has many analogies in population and socialsciences that could yield new insights into metastasis. In1829, R�ecamier recognized that cancer can spread from aprimary tumor and coined the term "metastasis" from theGreek "methistemi", meaning to change or displace (1).Paget’s "seed and soil" theory explained the nonrandompattern of cancer metastasis in 1889 when he postulatedthat factors within the metastatic site promoted growth inthe sameway that fertile soil allows the successful growth ofseeds (2). In a complementary hypothesis, James Ewingproposed in 1928 that cancer cells were directed to that siteby the direction of lymphatic and circulatory systems (3).

From the perspective of species migration, both Paget’sand Ewing’s theories are correct. Migration is subdividedinto emigration (the act of leaving), migration (the act oftravelling), and immigration (the process of arriving; ref. 4).In the paradigm of migration, Ewing focused on the migra-tion step, and Paget focused on immigration (2–4). Ewing’stheory accounts for the migration of prostate cancer cells tothe lumbar vertebrae via Batson’s plexus of draining lymphnodes, and Paget’s theory helps explain the organ specificityof prostate cancer metastases to bone. Fidler further refinedthe seed/soil hypothesis in 2003 to take into account theemigration step (5). First, primary tumors contain hetero-geneous subpopulations of cells with different angiogenic,invasive, andmetastatic properties (properties that promoteemigration). Themetastatic process is then selective for cellsthat can successfully survive migration to the distal targetorgan. The successful proliferation of metastatic cellsdepends on the ability of these cells to interact and use thesoil of the new microenvironment (5).

DiasporasDescribing metastasis in terms of migration alone is

insufficient to cover the nuances of cancer spread (Fig. 1).A diaspora, from the Greek diaspor�ameaning "scattering" or"dispersion", is the movement, migration, or scattering ofpeople away from an established homeland. To date, "dias-pora" has been applied exclusively to describe humanbehavior. In ancient Greece, a diaspora referred to citizensof a conquering city-state who colonized a conquered land

Authors' Affiliations: 1The James Buchanan Brady Urological Instituteand Departments of Urology, Oncology, Pharmacology, and MolecularSciences, Johns Hopkins School of Medicine, Baltimore, Maryland; 2Divi-sion of Science, Mathematics and Computing, Bard College, New York;and 3Department of Periodontics andOralMedicine, University ofMichiganSchool of Dentistry, Ann Arbor, Michigan

Corresponding Author: Kenneth J. Pienta, The James Buchanan BradyUrological Institute and Department of Urology, Departments of Oncologyand Pharmacology and Molecular Sciences, The Johns Hopkins School ofMedicine, 600 N Wolfe St, Baltimore, MD 21287. E-mail:[email protected]

doi: 10.1158/1078-0432.CCR-13-2158

�2013 American Association for Cancer Research.

ClinicalCancer

Research

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to assimilate the territory into the empire (6). Subsequent tothe Bible’s translation into Greek, "Diaspora" referred toJewish peoples exiled from Israel by the Babylonians in BCE587 and by the Romans from Judea in 70 CE (7). Since thattime, diasporahas come to refer tomassdispersions, usuallyinvoluntary, of people with common roots.

Diasporas share several common features that differen-tiate them from migrations. First, dispersal occurs to morethan one destination. By definition, a diaspora implies ascattering rather than a simple displacement fromone placeto another (8–11). This dispersal tomultiple destinations isa necessary step that eventually leads to the formation oflinks between the various populations of the diaspora. Inpopulation studies, a group is only considered a diaspora ifit first exits fromahomeland such that subgroups eventuallyexist across multiple national boundaries. Second, the scat-tered populations must continue to retain a relationshipwith the homeland. A diaspora exhibits ancestral memory –the dispersed population does not assimilate completelyinto the new environment, keeping a unique identity thathas roots in their original home. This results in a continuedunique identity for the dispersed population and allowsthe diaspora to exist over multiple generations and time.(9–12).

Metastasis Viewed as a DiasporaMetastasis is not a simple one-waymigration, but rather a

dynamic dispersal of cells that are inherently linked to theprimary tumor (Table 1). Although migrants are usuallyattracted to a new country and can come from single ormultiple origins, a diaspora is dispersed, usually expelled,from a single origin. At least early in tumorigenesis, beforethe establishment of multiple distant deposits of cancer

cells, metastases arise from a single site of origin, theprimary tumor (13). Several types of diaspora have beendescribed based on why the population scattered (14, 15).Which peoples moved and what segments of society left?Were they expelled, taken captive, or did they leavevoluntarily? Did they leave as a group all at once or asindividuals over a protracted period of time (15)? Theseemigrations have usually, but not always, been the result ofharsh economic conditions or other similar hardships(4, 9). Migratory diasporas may arise when individualstransit in and out of a host country but, in doing so,institutions and networks become established in the hostlands, for example, trading posts (15). It is becoming clearerthat cancers use the "trading post" diaspora analogy byforming premetastatic niches (16–18). Primary tumors,driven perhaps by hypoxic conditions, orchestrate the for-mation of premetastatic niches, in part, by the secretion of avariety of cytokines, growth factors, and exosomes to pro-mote mobilization and recruitment of bone marrow-derived cells to future metastatic sites (19–23).

The paradigm of the imperial diaspora also can beapplied to metastasis. As in the ancient Greece city-stateexample, diasporas originated as conquests, often resultingin subjugation of an indigenous population. Similarly,metastasis is generally considered to be an active processof cells leaving the primary tumor site (as opposed topassive sloughing of cells into the circulation), to colonizea target organ (19–23). In an imperial diaspora, the home-land is responsible for helping to maintain an interdepen-dent network of the diaspora. In turn, established coloniesnot only send resources back to the home country, but oftensend future generations back to the homeland for educa-tion, training, and cultural indoctrination. The exchange ofresources between dispersed communities and the homecountry is a key aspect defining a diaspora (24–26). Thisexchange of resources is often defined by the diasporacommunities sending economic support to the home coun-try as well as supporting the interests of the home countrywith the host countries on sociopolitical levels.

It appears that multiple host cells, including hematopoi-etic stem cells, mesenchymal stem cells, endothelial pro-genitors, cancer-associated fibroblasts, and inflammatorymononuclear cells (T and B cells and monocytes) trafficfreely between tumor sites (27–32). Furthermore, it hasbeen demonstrated in experimental systems that cancercells traffic between tumor sites within a host. Massagu�eand colleagues demonstrated that metastasis is a multidi-rectional process whereby cancer cells seed distant sites andreturn to the primary tumor itself (33–35). This self-seed-ing, at least in preclinical models, functions to facilitate andaccelerate tumor growth, angiogenesis, and recruitment ofstromal cells to the tumor microenvironments. Whetherbidirectional tumor movement does occur remains hotlydebated. Indirect evidence for the concept occurring inpatients can be inferred from work on disseminated tumorcells (DTC) in patients with breast cancer. Pantel andcolleagues have demonstrated that the presence of DTCsin bone marrow at initial diagnosis predicts local and

Translational RelevanceMetastases remain the major reason for the morbidity

and mortality associated with cancer death. Describingmetastasis as a simple migration of cells from the pri-mary to target organs is insufficient to understand thenuances of cancer spread. To date, "diaspora"—thescattering of people away from an established home-land—has been applied exclusively to describe humanbehavior. The application of the diaspora concept canalso be applied to metastasis, which together with eco-logic principles may help to develop new treatmentstrategies. For example, ecologic traps—habitats thatlead to species extinction—can be developed to attractcancer cells to a place where they can be better exposedto treatments or to cells of the immune system forimproved antigen presentation. Merging the social sci-ence concept of diaspora with ecologic and populationsciences concepts can inform the cancer field to under-stand the biology of tumorigenesis and metastasis andinspire new ideas for therapy.

Pienta et al.

Clin Cancer Res; 19(21) November 1, 2013 Clinical Cancer Research5850




metastatic relapse (36–39). These investigators havedetected circulating tumor cells (CTC) in patients withearly-stage breast cancer months after primary tumor resec-tion, suggesting that CTCs are derived from occult micro-metastases (39).Another critical aspect to understand the dynamics of

diaspora development is the area that becomes the newhome for the displaced population. For a displaced people,the ability and willingness for the host country to allowimmigration is a key step in the formation of the diaspora.This is dependent on physical characteristics (i.e., is thereroom, ability for the population to thrive economically) aswell as sociopolitical characteristics (i.e., willingness of thehost community to accept the displaced peoples; refs. 24–26). This is analogous to the favorable soil described byPaget (2, 5).Boundary maintenance is another important criterion of

a diaspora (24). Both migrant and diaspora communities

maintain a collective memory of their homelands asreflected by continuing to celebrate their ethnic roots. Thediaspora community, however, must maintain an identitywithin the host country over time. In contrast to manymigrant populations, a diaspora group does not assimilateinto the host population butmaintains a distinct identity asmuch as is possible. Cancermetastases are easily recognizedin the target organ, most often observed as masses withdistinct boundaries (40). This boundarymaintenance blursin migrant populations. The relationship of migrant popu-lations with the host country tends to improve over time asthe migrants assimilate into the host communities. Thediaspora relationship with the host community tends toremain complicated andoftenuneasy, andbetter reflects therelationships of a metastatic deposit with the target organ.The metastatic deposits maintains its identity and is intension with the host immune and other defense mechan-isms which strive to limit growth (41, 42).

Cancer cells

Host cells

Soluble factors(e.g., exosomes,

cytokines, hormones)

Figure 1. The cancer diaspora.Describing metastasis in terms ofmigration alone is insufficient tocover the nuances of cancerspread. The diaspora paradigmtakes into account and modelsseveral variables: the quality of theprimary tumor microenvironment,the fitness of individual cancer cellmigrants, as well as migrantpopulations, the bidirectionalmovementof cancer, andhost cellsbetween cancer sites (includingbetween primary and metastasesas well as between metastases),and the quality of the targetmicroenvironments to establishmetastatic sites.

The Cancer Diaspora: Refining the Concept of Metastasis

www.aacrjournals.org Clin Cancer Res; 19(21) November 1, 2013 5851




Diasporas, Metastases, and EcosystemsBroadening the concept of diaspora and simultaneously

applying ecologic scientific principles facilitates a broaderunderstanding of the dispersal of cancer cells (43–45). Forexample, a metapopulation consists of a group of separatedpopulations of the same species that interact at some level.Metapopulation dynamics can be applied to any species infragmented habitats; much like a diaspora from a singlepoint of origin to multiple host countries. Although cancermetastases may be thought of as metapopulations, they areactually metacommunities. Metastases are made up of mul-tiple species of tumor and host cells interacting dynamical-ly. Metacommunities are a network of local communitiesthat are linked through multiple potentially interactingspecies or populations. Metapopulation and metacommu-nity dynamics allow us to study not only the growth andinteractions of individual populationswithindifferent sites,but also the interactions and connectivity between sites(46).

Understanding the dispersion ofmetastatic cancer cells tosites throughout the body from a site of origin may use thetheoretical ecology model of source-sink dynamics todescribe how variation in habitats [both homeland (the"source" of species) and host land (the "sink" or habitat towhich species migrates)] affect population growth ordecline inmetapopulations (47). Source-sink dynamics canhelp model how individual populations flourish or declineamong different patches of habitat, for examples, a high-quality habitat that on average allows the population toincrease or a low-quality habitat that, on its own, would notbe able to support a population (referred to as a sink).Habitat quality is quite analogous to the concept of fertile orpoor soil as delineated by Paget (2). Moreover, source-sink

models take into account how population numbers vary–that an excess of individuals often move from a source(primary tumor) and can continue to supply other sites(new seeds; refs. 33–35).

The rate of by which a cancer establishes its diaspora is,therefore, dependent on several variables (Table 2). (i) Thequality of the primary (homeland or origin) microenviron-ment – themore likely themicroenvironment is oxygenatedand with a sufficient source of nutrients, the less likelycancer cells will be driven to engage cellular programs thatpromote extravasation/emigration. (ii) The rate of passiveand active emigration is another variable. Emigrant cancercell populations can be divided into cells that passivelyslough into the circulation and cells that actively extravasateinto nerves, lymphatics, or blood. It is likely that passiveemigrants may not have all of the machinery necessary tosurvive to successfully migrate. Cells that have been forcedto undergo an epithelial to mesenchymal transition (EMT)in response to a hypoxic environment aremuchmore likelyto survive a migration. (iii) The quality and number of thetarget organ (host-land) microenvironments is anotherimportant variable. The quality of the soil is well documen-ted as a critical component of successful metastasis.

Previously, it was thought that cancer cells could notdifferentiate between different target organs and the processof seeding was thought to be agnostic, that is, just as manycells would land in the lung as the bone depending onblood flow, etc (48). New data suggests that this is mostlikely untrue on both the seed and the soil sides of themetastasis argument. First, cancer cells can carry receptorsfor antigens on particular cell types, that is, prostate cancercells have a high level of Annexin II which allows binding toosteoblasts in the endosteal niche of the bone marrow

Table 1. A comparison of migrants, diaspora, and cancer metastases

Social demographyCancer demography

Migrant communities Diaspora communities Cancer metastasis

Moved from a single or multipleprimary homelands

Dispersed from a single homeland Dispersed from a primary cancer

Attracted to new country Pushed from homeland Hypoxia and lack of nutrients causespressure to leave primary

Host country may or may not bereceptive

Host country may or may not bereceptive

Target organ receptive

Group maintains collective memoryof their homeland and culture

Group maintains collective memoryof their homeland and culture

Pathologists can identify where acancer cell originated

Often assimilate into the newhomeland

They wish to survive as a distinctcommunity

Metastases as distinct masses

Relationship with host country iscomplicated and uneasy butimproves over time

Relationship with host country iscomplicated and uneasy

Immune system tries to destroy thecancer cells

May or may not be tied to thehomeland by exchange ofresources

They are tied to their homeland atmany levels – exchange ofresources (economic,sociopolitical)

Multiple cell-type trafficking,trafficking of resources/info

Pienta et al.





(19, 49). Second, the elegant work of Wang and colleagueshave suggested that bone marrow-derived mesenchymalcells organize premetastatic niches (trading posts in thediaspora analogy) that provide a better soil than mayactually attract cancer cells, allowing them to distinguishbetween high- and low-quality habitats (18). The source-sink model implies and models that some habitat patchesmay be more important to the long-term survival of thepopulation and can be modeled by their demographicparameters or rates of birth, immigration, death, and emi-gration (BIDE; ref. 47).

UsingCancerDiaspora –EcosystemConcepts toTarget MetastasisViewing cancer within the context of ecology can lead to

therapeutic paradigms based on network disruption acrossthe scale of ecosystems from the cell through to the hostpatient (46). The diaspora concept adds to this analogy byspecifically expanding this therapeutic paradigm as cancercells metastasize and establish metacommunities. Onepotential therapeutic strategy would be to create ecologictraps (50–52). Ecologic traps are poor-quality habitats thatare highly attractive to wildlife species based on environ-mental cues that typically signify a high-quality habitat(50). This type of cue is analogous to signals which cancercells receives to settle in a specific target organ. Van derSanden and colleagues have suggested that neurotransmit-ters could be used to attract glioma cells to settle in alocation where treatments (e.g., drugs, radiation, surgery)

can be effectively or safely concentrated (near the surface,away from sensitive tissues, within surgically implantedtissue or material). Instead of preventing metastasis, such‘attracticides’ serve as "‘guides" to facilitate cancermigrationtoward poor-quality habitats where cancer cells can beeliminated (50).

Using traps to treat cancer is analogous to altering theecologic landscape of interactions in the body in ways inwhich the cells are unable to anticipate or react to and thatare ultimately invisible to them. Corollaries of this strategyinclude placing familiar ‘cues’ in places that lead to theextinction of cancer cells, or masking attractive cues infavorable microenvironments. For glioma cells, a reservoirof neurotropic chemokines could be used to attract cancercells to an area where they could be irradiated (51). Forprostate cancer cells, a reservoir of SDF-1 could be tempo-rarily inserted intravenously to attract the cells into a one-way trap (53).

Furthermore, an ecologic trap could be constructed toexpose cancer cells to cells of the immune system, leading toincreased antigen presentations (52), or disrupt the abilityof metastasizing cells to recruit appropriate host cells.

Our ability to manipulate the primary tumor or dissem-inated tumor cells in a diaspora remains limited. Itwould beideal to develop strategies to halt the emigration of tumorcells from the primary tumor (homeland) or to mask theattractiveness of the target organs (host lands). Perhaps, wecould even use this strategy to ‘recall’ disseminated tumorcells to the primary ‘homeland" to facilitate a more focusedand strategic therapy. The technology to create artificial

Table 2. Development of equations may help to define the rate and success or failure of a cancer diaspora

Cancer dispersion Quality of primary microenvironment Fitness of migrant cancer cells Quality of metastatic sites

Cancer diaspora ¼ [PDQDt] [EMDt] [(EFnDt)þ(MFnDt)][TR] [(H1Qn))þ (H2Qn)). . .]

Primary microenvironment (homeland) factors:ODQDt¼ the quality (Q) of the primary cancer site (P). Cancer cells in a highly vascularized environment with rich nutrients are presumedto be less likely to undergo an epithelial to mesenchymal transition (EMT) and leave the primary.

EMDt ¼ generation of cancer cells (tumor cell heterogeneity) over time (Dt). Epithelioid cancer cells (E) are less likely to be able tometastasize as compared with mesenchymal cancer cells (M).

Migration factors:EFnDt ¼ the number (n) and fitness (F) of passively shed cancer cells (E) over time (Dt). This represents the likelihood that a cancer cellpassively shed into the circulation will survive transport to a target organ. It is likely that the fitness of a passively shed cell is less than acell that actively exits the primary tumor through the lymphatics, nerves, or circulation.

MFnDt¼ the number (n) and fitness (F) of actively emigrant cancer cells (M) over time (Dt). This represents the likelihood that a cancer cellthat actively extravasates into the circulationwill survive transport to a target organ. Fitness depends onmany variables, including EMTstate, ability to secrete MMPs, ability to avoid anoikis, etc.

TR ¼ transit resistance factors. This represents factors in the circulation that inhibit migration, including shear forces and the hostimmune response that destroy cancer cells.

Target organ (host-land) factors:HQ n¼ the quality (Q) of the target organ or host-land sites (H1, H2. . .). Migrating cancer cellswill land inmultiple sites (n) within differenttarget organs in order to immigrate. Success depends on the quality of the soil of each of these microenvironments. Prostate cancercells, for example, are more likely to flourish in a high-quality bone microenvironment than a low-quality habitat such as the lungmicroenvironment.






tissue traps or synthetic microenvironments already doesexist (52). Another approach to killing cancer cells may beto force a diaspora from their metastatic sites where theymay be protected from therapeutic intervention. For exam-ple, Shiozawa and colleagues have demonstrated that pros-tate cancer cells can be mobilized out of the bone marrowmicroenvironment and into the unprotected circulationwhere they may be easier to target (49). Recognizing thatgenetic diversity among tumor cells to respond to differentattractants is most likely, the creation of multiple evolu-tionary traps within a device providing multiple chemo-kines and/or metastatic niches should be considered (20–23, 50). The recent discovery that cancer cells continue tocirculate after they metastasize suggests that this approachmay offer therapeutic benefit even in patients withadvanced disease (33–39). Together, these concepts dem-onstrate that merging the social science concept of diasporawith ecologic and population sciences concepts can inform

the cancer field to understand the biology of tumorigenesisand metastasis and inspire new ideas for therapy.

Disclosure of Potential Conflicts of InterestNo potential conflicts of interest were disclosed.

Authors' ContributionsConception and design: K.J. Pienta, R.S. TaichmanDevelopment of methodology: K.J. PientaWriting, review, and/or revision of the manuscript: K.J. Pienta,B. Robertson, D. Coffey, R.S. TaichmanAdministrative, technical, or material support (i.e., reporting or orga-nizing data, constructing databases): K.J. Pienta

Grant SupportThis work is financially supported by the NCI (grant no. U54CA143803

to K.J. Pienta, D. Coffey; grant nos. CA163124 and CA093900 to K.J.Pienta, R.S. Taichman; and grant no. CA143055 to K.J. Pienta).

Received August 6, 2013; revised September 6, 2013; accepted September13, 2013; published OnlineFirst October 7, 2013.

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2013;19:5849-5855. Published OnlineFirst October 7, 2013.Clin Cancer Res Kenneth J. Pienta, Bruce A. Robertson, Donald S. Coffey, et al. HypothesisThe Cancer Diaspora: Metastasis beyond the Seed and Soil

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