Stem cell&cancer


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Stem cell&cancer

  1. 1. Seminars in Cancer Biology 17 (2007) 191–203 Review Stem cells and cancer JeanMarie Houghton a,∗ , Alexei Morozov b , Iva Smirnova b , Timothy C. Wang b a Department of Medicine, GI Division (JH), Department of Cancer Biology, University of Massachusetts Medical School, LRB-Second Floor, Room 209, 364 Plantation Street, Worcester, MA 01605-2324, United States b Division of Digestive and Liver Diseases (TCW), Columbia University Medical Center, Irving Cancer Research Center, 1130 St. Nicholas Avenue, Room 925, 9th Floor, New York, NY 10032, United StatesAbstract The cell of origin of cancer has been a strongly debated topic through out the history of cancer research. This review provides a historic frameworkand a synopsis of how the theories of cancer initiation and progression evolved from early times to the present day. We present the concept of acancer stem cell, and review for you the literature supporting the existence of cancer stem cells in addition to a brief discussion on our own worksupporting a bone marrow-derived source for the cancer stem cell, as well as cells of the cancer stroma.© 2006 Elsevier Ltd. All rights reserved.Keywords: Cancer stem cells; Bone marrow-derived cells; Mesenchymal stem cells; Gastric cancer; Mouse models of cancer; Helicobacter disease; Inflammation;Neovascularization; Tumor stromaContents 1. Origin and history of stem cell theory of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 191 2. Current definitions of stem cells and the stem cell niche . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 192 3. Stem cell origin of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 193 4. Bone marrow-derived stem cells . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 5. Chronic inflammation and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 194 6. Gastric cancer: Helicobacter induced chronic inflammation and the progression of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 195 7. Metaplasia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 196 8. BMDC origin of gastric cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 197 9. Stem cells in tumor stroma and tumor angiogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 10. Why not a gastric stem cell? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 198 11. Fusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 12. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 200 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2001. Origin and history of stem cell theory of cancer globules, which he called “cells”, had the capacity to multiply independently, making them true “citizens of the organism”, German pathologists headed by Johannes Muller in the 1840s which he referred to as a “cell-state”. He postulated that tumorwere the first to examine tissue sections under high magnifi- cells must come from normal cells, hence omni cellula e cel-cation and by doing so founded the field of pathology. Sub- lula or “every cell from a cell” [1]. Julius Cohnheim, anothersequently, three pupils of Muller began to study the origins of pupil of Muller, took a different approach, and in 1867 pro-tumors. Rudolf Virchow was the first to recognize that only small posed that tumors are derived not from normal adult tissues, but from “embryonal cell rests”, which he described as resid- ual embryonic cells “left behind” in the adult organism [2]. ∗ Corresponding author. Tel.: +1 508 856 6441; fax: +1 508 856 4770. Finally, Wilhelm Waldeyer in a series of detailed and highly E-mail addresses: (J. Houghton), convincing papers proposed that carcinomas were derived (T.C. Wang). adult epithelial structures [2] placing the cell of origin of cancer1044-579X/$ – see front matter © 2006 Elsevier Ltd. All rights reserved.doi:10.1016/j.semcancer.2006.04.003
  2. 2. 192 J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203in his theory within the differentiated epithelial or endothelial Julius Cohnheim’s theory of embryonal cell rests was beginningcompartment. to be resurrected. In parallel with these studies and spanning two centuries, thegenetic basis of cancer was elucidated, beginning with PercivalPott’s early observation of increased testicular cancer in chim- 2. Current definitions of stem cells and the stem cellneysweeps which linked environmental exposure to cancer, and nicheculminating in mutagenesis assays developed by Ames, whichdemonstrated that cancer was caused by genetic mutations [3]. In the 1950s it was discovered by radiation biologists thatThe question remained—how many mutations, and in what cell? lethally irradiated mice could be rescued from an inevitableWilhelm Waldeyer’s theory predicted that any cell in the given death by reintroduction of whole bone marrow (BM) cells [11].organ could give rise to a tumor. In humans, over 1011 new cells Till and McCulloch [12] noted that the reestablishment of a func-are generated every day. With a mutation rate of about 10−6 per tional hematopoietic system was accompanied by the formationgene, per cell generation [4], millions of cells carrying random of colonies in the spleen, and these colonies contained cellsmutations in every gene are generated daily, however, tumors capable of establishing additional colonies when reinjected intoare a relatively rare event. To resolve this seeming contradic- second mouse [13]. Based on these seminal studies, the authorstion, the multistep tumorigenesis theory was developed. It was proposed for the first time a strict definition of a “colony-formingproposed that multiple independent events must occur in a sin- cell”, later to become the definition of a stem cell: the capacity ofgle cell, with the probability of each event proportional to the self-renewal and the capacity of forming differentiated progenyage of the individual [5,6]. This multistep tumorigenesis theory [13–15]. Research into the biology of hematopoietic stem cellsfocuses on the nature and number of mutations, rather than on the (HSCs) eventually led to their purification to homogeneity [16],properties of the cell in which they occur. Despite a number of and the widespread use of HSC in clinical medicine for marrowlimitations, the principles and concepts of this theory have been reconstitution.incorporated into the current paradigm of cancer research. How- The notion of a stem cell giving rise to an array of differ-ever, the exponential rise of cancer incidence with age has not entiated cells thus sustaining the integrity and function of thebeen supported by more detailed epidemiological data, where hematopoietic system spread to encompass other organ systemsfor many cancers, incidence peaks at a certain age and declines and to the organism as a whole. Stem cells are now thoughtthereafter. For example, retinoblastoma and Wilm’s tumor are to span a spectrum from cells of the zygote through embryonicsolely pediatric cancers, while testicular cancer peaks at age 35, stem cells to more lineage-restricted adult tissue stem cells. Stemthyroid cancer at age 60, breast cancer at age 80 [7]. Knud- cells purified to near-homogeneity include mammalian neuralson, through his work on retinoblastoma, proposed that familial crest cells [17,18], CNS stem cells [19], skin stem cells [20,21],predisposition to retinoblastoma was due to inheritance of a ger- skeletal muscle stem cells [22] and mammary cells [23,24]. Inminal mutation and tumors develop as a result of an additional other adult tissues progenitor cells have been indirectly defined,somatic mutation in a susceptible retinal cell carrying this muta- and these include cells of the gut, liver, pancreas, and the gonadstion [8]. Thus, the notion began to emerge that mutations give [25]. In many organs, such as the stomach, stem cells are poorlyrise to cancer only if they occur in the appropriate cell type. It defined [26].can be reasoned that since most cells in the body are terminally Despite the tremendous enthusiastic search for tissue stemdifferentiated and post-mitotic, they would either not survive cells of peripheral organs, there has not been the success seen inlong enough to gain sufficient mutations to become malignant. the BM field. The literature to date describing peripheral stemTherefore, cells with extended proliferative potential are likely cells or candidate cells has severe limitations. In order to identifyat highest risk of evolving into a tumor [4]. a tissue stem cell, one needs to demonstrate that the cell is able The concept of a less differentiated, more pluripotent (stem) to recreate or sustain tissues (e.g. an epithelium) in vivo, at thecell forming cancer was taken a step further by Pierce [9], single cell level and cells must maintain these properties in serialwho studied mouse teratocarcinomas. Individual tumor cells transplantations [27]. To date, this has not been achieved for thewere capable of forming normal, non-malignant progeny when vast majority of candidate stem cells.transplanted into another host, leading him to speculate that While many mysteries remain, several fundamental proper-the tumor contains a small number of “malignant stem cells” ties of stem cells have been delineated. First, stem cells arethat maintain stem cell function yet give rise to daughter cells thought to exist in a unique microenvironment referred to aswith varying degrees of differentiation and function. Potter [10] the stem cell niche, a concept first proposed by Schofield [28].demonstrated the presence of embryonal biochemical markers Indeed, the development of hematopoietic stem cells is depen-in mouse and human hepatomas leading him to conclude that dent on neighboring osteoblastic cells [29], Drosophila germhepatoma cells are arrested in their development and this differ- stem cells rely on surrounding somatic cells [30] for growth,entiation block may contribute to tumor formation: “oncogeny is and in the mammalian hair development model, hair follicle stemblocked ontogeny” [10]. Thus, the proposed identity of the can- cells exist within a structure known as the follicle bulge [31].cer initiating cell came full circle, beginning with the concept In fact, in the Drosophilia system, stem cells may be somewhatthat a terminally differentiated cell was responsible, progressing interchangeable, with the ultimate lineage commitment and dif-to the acceptance that an immature progenitor cell was respon- ferentiation patterns determined primarily by the niche rathersible for tumor initiation. Thus, a century after it was proposed, than the cell itself.
  3. 3. J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203 193 Stem cells within a niche are present in small numbers and heterogeneous mixture of tumor cells at various levels of dif-remain largely quiescent, undergoing division at a very slow rate ferentiation, very similar to the structure of an organ, albeit[32,33]. The stem cells divide, producing one identical quiescent an abnormal organ. Next based on both in vivo and in vitrodaughter cell and one transient amplifier cell which is respon- tumor studies, came the observation that only a small fractionsible for the bulk of cell division. Transient amplifying cells of cells within a tumor possess self-renewal capacity [41,42]. Itappear to have a limited lifespan, and are replaced periodically can be argued that while all cells within a tumor are equal, atby the true stem cell. This mechanism of maintaining the stem any given time only a small fraction of cells is in an appropri-cell in a relatively dormant state protects the genome from muta- ate state or stimulated by appropriate external signals to formtions, while delegating the genetically dangerous task of repeat a new tumor. Alternatively, it can be reasoned that there is areplication to a dispensable cell. The slowly cycling property of predetermined population of cells with the “cancer stem cell”stem cells also allows them to retain DNA labels (such as BrdU) phenotype, enabling this cell to perpetuate the tumor, whilelonger than most cell types, a property commonly exploited to other cells of the same tumor are incapable of self renewal.isolate stem cells prospectively as label-retaining cells (LRCs). To prove the latter would require prospective isolation of thisThe stem cell niche is believed to be largely responsible for this population. Indeed, this was done by John Dick’s group, whoslow cell division, protecting the vulnerable stem cells (and their demonstrated that cells capable of establishing a human AMLgenetic material) from damage or exhaustion, and protecting the phenotype in a recipient mouse were isolated only within thehost from unregulated stem cell outgrowth [4,34]. cell fraction expected to contain the hematopoietic stem cells, Recently, the identification of circulating progenitor cells defined by the CD34+ CD38− phenotype [43]. Further, thesecapable of functioning as lineage specific stem cells (such as cells could be passed from animal to animal and maintain theendothelial progenitors) calls into question whether distinct AML phenotype [44], confirming the property of self-renewal.and unique stem cell populations exist for each organ or tis- Thus, it was demonstrated for the first time that there are cellssue, or if a more centralized source of stem cells exists, with within the tumor which have properties similar to stem cells, i.e.the organ specific niche the ultimate determinant of stem cell the capacity to reconstitute the tumor when transplanted into anfunction. appropriate recipient (differentiation) through several rounds of transplantation (self-renewal).3. Stem cell origin of cancer Similar approach has led to the identification of subpopu- lations of tumor cells with stem cell properties within breast If the role of stem cells in normal tissue turnover is incom- tumors [45], gliomas [46–48], melanoma [49], prostate can-pletely understood, even less is known about stem cells in cer [50] and osteosarcoma [51]. These observations have ledmalignancy. This subject has been a topic of several excellent to the “cancer stem cell hypothesis” [35] which postulates thatreviews [35–40]. The concept that stem cells function in tumors within a tumor, a small proportion of cells with unlimited pro-has a basis in several observations. Tumors are composed of a liferative capacity drive tumor growth (Fig. 1A). This modelFig. 1. Impact of cancer stem cells on tumor growth and response therapy. (A) A subset of cells within a tumor has the ability to replicate and sustain tumor growth.These cancer stem cells give rise to identical immortal daughter cells (red) and transient amplifying cells (TA-white). It is the TA which is believed responsible forthe bulk of tumor cell proliferation, and is the cell type susceptible to the cancer therapy. (B) Possible outcome of targeting tumor stem cells verses conventionaltherapy which does not affect the stem cells.
  4. 4. 194 J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203fits with the observation that most cancers comprise a heteroge- in many organs including the heart [58]; skeletal muscle [62] orneous population of cells that have undergone varying degrees the kidney [63]. Therefore the questions of exact contribution ofof differentiation. Also in line with this observation is the fact bone marrow-derived cells to the turnover of normal adult tis-that conventional therapies which target actively dividing cells sues, and whether stem cells are able to cross tissue boundaries,may substantially reduce tumor bulk, but often times do not pre- await more detailed experiments using purified cell populationsvent tumor re-growth; presumably because conventional therapy and careful cell marking techniques.does not destroy the cancer stem cell (Fig. 1B). Thus, there are It has been suggested that the apparent stem cell plasticityparallels between cancer stem cells and normal stem cells, and may be explained by fusion between a BMDCs and a peripheralbetween tumors and normal organs. cell [64–66]. This has been demonstrated convincingly in the liver and muscle, and may represent a phenomenon unique to4. Bone marrow-derived stem cells these organs, and further may require a severe degree of damage. In other tissues the bulk of evidence suggests that true differen- Accumulating data support the notion that adult bone marrow tiation of BMDCs to a tissue specific cell phenotype occurs andstem cells have a surprising degree of plasticity, contradicting phenotypic changes are not due to fusion [67].the conventional view that bone marrow stem cells give riseonly to formed elements in the peripheral blood (hematopoi- 5. Chronic inflammation and canceretic stem cells, HSCs) and of the marrow stroma (mesenchymalstem cells, MSC). Multiple studies from independent groups Given the role of inflammatory mediators in mobilizing stemhave demonstrated that bone marrow cells can differentiate cells and modulating cancer risk, some attention must be givenalong endoderm, mesoderm and ectoderm lineages, a decision to the subject of chronic inflammation. The relationship betweendependant upon the environment in which these cells engraft. chronic inflammation and cancer has long been recognized. InThe discovery of circulating pluripotent adult stem cells has 1863, Virchow hypothesized that the origin of cancer was at sitesgenerated excitement regarding their possible therapeutic use, of chronic inflammation [68]. Although some interpreted thisas well as provided us with another candidate for the cancer association as suggesting that the leukocytes were attemptingstem cell. to eradicate neoplastic cells, more recent studies have indicated Initial animal studies by Lagasse et al. [52] detailed the abil- a role for inflammatory cells in actually promoting the pro-ity of bone marrow-derived cells to repopulate injured liver and gression of many cancers. Cancer has long been viewed as “thecontribute to liver regeneration. Subsequent studies have sup- wound that will not heal” [69] and epidemiologically, chronicported plasticity of adult circulating progenitor cells (reviewed inflammatory disorders show a strong association with cancerin Ref. [53]) which reside in the periphery as isolated single risk. Many if not most malignancies are initiated by tissueepithelial cells within the lung, gastrointestinal tract (esopha- injury or chronic inflammation, which can be linked to knowngus, small intestinal villus, colonic crypts and gastric pit of the bacterial, viral or parasitic infections [70]. Overall, approxi-stomach) and skin [54]. Early studies evaluated whole BM, sub- mately 15% of malignancies worldwide (1.2 million/year) cansequent studies indicate this is likely a property of mesenchymal be attributed specifically to chronic infections, and examplesstem cells [55]. include bladder cancer due to schistosomiasis, liver cancer Human studies have confirmed that bone marrow-derived due to Hepatitis B and C infection, cervical cancer due tostem cells (BMDCs) can differentiate into mature hepatocytes human papilloma virus, and gastric cancer due to Helicobacterand skin/gut epithelial cells [56] and can substantially repopulate pylori (H. pylori). Many other cancers are initiated by chronicthe GI tract (up to 7% of intestinal/liver cells) during epithelial inflammation secondary to other etiologies, such as esophagealregeneration after graft-versus-host disease or healing of severe adenocarcinoma due to gastroesophageal reflux, colon cancerulceration [57]. Interestingly, in human and mouse model sys- due to inflammatory bowel disease, and lung cancer due totems, the degree of repopulation of organs by BMDCs is closely smoking. These examples represent the “tip of the iceberg”,related to the degree of tissue inflammation and injury. In a para- since most cancers do not arise in a normal tissue environmentbiotic mouse model, employing one mouse with marked marrow, but require some initial degree of tissue alteration.and one without marked marrow, there was no demonstrable Polymorphisms in genes encoding pro-inflammatoryengraftment of BMDCs after several months [58]. However, this cytokines are increased in individuals with an increased risk ofwould be expected if chronic inflammatory or severe injury is cancer. In addition, the presence of specific immune cells – suchrequired for engraftment. The present data suggests that it is as macrophages and mast cells – in and around neoplastic tissueunlikely that BMDCs contribute to organ maintenance under has been associated with a poor prognosis. Population-basednormal conditions, but may serve as a backup or “second line of studies show that susceptibility to cancer increases when tissuesdefense” in situations of severe injury and repair. are chronically inflammed and long-term use of NSAIDs There are however, a number of limitations in these stud- reduces the risk of many cancers, further demonstrating theies [59–61]. Most bone marrow transplantation studies have not importance of inflammation in the pathogenesis of cancer.used single cells or purified cell populations and have not doc- The classical model for inflammation and cancer suggestsumented whether donor-derived cells become fully functional that chronic inflammation leads to increased oxidative stress,when they incorporate into donor tissues. Also, no quantitatively whereby leukocytes induce DNA damage in proliferating cellssignificant contribution from the bone marrow has been detected (through generation of reactive oxygen and nitrogen species
  5. 5. J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203 195normally produced to fight infection), leading to accumula- 6. Gastric cancer: Helicobacter induced chroniction of mitotic errors and promotion of epithelial cancers that inflammation and the progression of cancerhave been initiated. Inflammatory cells secrete numerous pro-inflammatory cytokines, growth factors and matrix-degrading H. pylori has been designated as a World Health Organizationenzymes. This abnormal milieu promotes apoptosis of normal class 1 carcinogen for its role in inducing both gastric adeno-cells leading to a compensatory proliferative response by the carcinoma and primary gastric lymphoma [83]. Because of thisremaining tissue. Thus, chronic injury or inflammation over strong association and the availability of robust mouse models ofdecades leads to a sustained expansion of tissue proliferative disease, Helicobacter induced gastric cancer is an ideal modelzones and predisposes to neoplastic progression [71]. However, system to address the precise mechanism by which a chronicthese elevations in chemokines and cytokines induce not only infection/inflammatory condition leads to cancer.monocyte/leukocyte migration but also influence cancer cells Bacterial factors have been intensely studied for their role inand interestingly, bone marrow stem cells [68]. Indeed, similar initiating disease (we refer you to several reviews on bacterialto white blood cells, many types of BMDCs are mobilized into virulence [84,85]). H. pylori is unique in its ability to colonizethe circulation in response to inflammatory mediators [72,73]. the gastric mucosa, and indeed, it is the only bacterium which Recent work suggests that inflammation may contribute to all is able to survive in the acid environment of the stomach. Afterthree stages of carcinogenesis (initiation, promotion, and pro- years of infection, the acid producing mucosa becomes atrophicgression) [74]. In addition, accumulating evidence suggests that and acid production dramatically decreases. Under these condi-immune cells can foster tumor development. Macrophages and tions, other bacterial species usually found in the small intestinerelated myeloid lineages such as tumor-associated macrophages are able to survive in the gastric musosa causing an inflam-(TAM), in particular, play a critical pathogenic role in many matory response. Interestingly, we do not yet fully understandtumors. These inflammatory cells of the innate immune sys- how the bacterium is recognized by the host innate immune sys-tem are recruited to the tumor microenvironment, where they tem. There is evidence to support a role for pattern recognitioncontribute to the regenerative “niche” [75] and exert pro- receptors (Toll-like receptors or TLRs) in the initial response totumorigenic effects [68,71]. Accordingly, in many human Helicobacter colonization [86], however, there is not yet a con-tumors, the infiltration of macrophages is associated with a sensus on which receptor within this group is most important,poor prognosis, and numerous studies, including studies in gas- or which cell type expressing the receptor plays the central roletric cancer [76], have shown a correlation between macrophage in antigen recognition. Despite the unclear initiating events, it isinfiltration and tumor vascularity and progression. In addition, certain that chronic inflammation is necessary for the progres-elimination of macrophages using CSF-1 null mice showed that sion through atrophy to gastric cancer.macrophage recruitment is important for progression of mam- Mouse models of infection have proven extremely useful inmary gland tumors, since invasive growth and metastasis were the study of Helicobacter pathogenesis with different strainssignificantly attenuated [77,78]. In addition to enhancing vascu- developing disease at different rates and severity. The C57BL/6larity and growth, these macrophages may suppress local T cell mouse appears to be the most susceptible and to most closelyresponses [79]. However, some T cell subsets also contribute to recapitulate human disease. Early on in infection, there is antumor development, and studies employing models of skin car- increase in apoptosis followed by an increase in proliferationcinogenesis have indicated that mice deficient in CD4+ T cells with resultant loss of parietal and chief cells (atrophy), intesti-show a delayed neoplastic progression and a lower incidence of nal metaplasia, and finally dysplasia followed by invasive gas-tumors [80]. tric cancer by approximately 15 months of age [87]. Infection Overall, the progression of several types of cancer is deter- in recombinase activating gene (RAG) deficient mice, severemined primarily by the severity of the inflammatory response, combined immunodeficiency (SCID), and T cell-deficient micewhich may be regulated by NF-kB, since many of the key pro- fails to produce tissue damage, cell lineage alterations or theinflammatory cytokines – such as IL-1b, TNF-a, IL-6 and IL-8 metaplasia–dysplasia–carcinoma sequence [88,89]. On the other– are encoded by target genes of the IKKb-dependent NF-kB- hand, infection in B cell-deficient mice (which retain a normalactivation pathway. Recent studies from Karin’s group have T cell response) produces severe atrophy and metaplasia, identi-finally demonstrated in vivo the importance of macrophage- cal to what is seen in infected wild-type mice, stressing a crucialderived NF-kB expression [81]. In this study, disruption of the role for CD4 T lymphocytes in orchestrating disease. Suscepti-NF-kB pathway in myeloid cells resulted in a strong (50%) ble strains (such as the C57BL/6) mounts a strong Th1 responsereduction of cancer in an ulcerative colitis (i.e. DSS) associated [90,91] while resistant strains such as the Balb/C respond withmodel of colorectal cancer associated with a marked reduction a polarized Th2 response and appear protected from mucosalin expression of IL-1b, IL-6, and MIP-2. A similar reduction damage despite maintaining bacterial colonization [90] stronglyin tumor incidence was seen when IKKb was deleted in the supporting a role for the cytokine environment in dictating dis-myeloid lineage in a mouse model of hepatocellular cancer ease. Strains such as the C3H show intermediate disease suscep-[82]. tibility. The C3H strain has a mixed Th1/Th2 cytokine profile, Overall, the majority of evidence suggests that NF-kB pro- suggesting that cytokines within an immune response interact tomotes cancer by inhibiting apoptosis of cancer cells and upreg- form a continuum of disease rather than discrete disease states.ulating numerous cytokines and growth factors which sustain The different response to infection between strains as well ascancer growth. progression through distinct mucosal alterations in the C57BL/6
  6. 6. 196 J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203mouse (akin to what is seen in human disease), make the murine replication. This delicate balance is dramatically altered withmodels of infection extremely powerful tools to explore disease infection, when initially the levels of apoptosis increase at leastmechanisms. in part, through upregulation of the Fas/FasL pathway [97] and While it is most likely that the aggregate immune environ- occurs in a non-random fashion. Parietal cells, and to a lesserment most likely dictates disease manifestations, there may be extent chief cells are preferentially susceptible to this apoptotica role for individual cytokines in both the predisposition to and signaling. This is followed later by an increase in prolifera-protection from disease. The IFN-␥ knockout mouse illustrates tion and homeostasis is maintained at the cost of increased cellthis point, where lack of IFN-␥ protects infected mice from turnover. The trigger for proliferation may be multifactorial, andatrophy [90,91]. On the other hand, the knockout of IL-10, a may be a physiologic response to the increased cell loss, or ascytokine whose main function it to modulate and dampen down data from our laboratory suggests, the result of differential sig-an immune response, leads to severe atrophic gastritis [90,91]. naling through the Fas pathway [98] in cells expressing a lowerAdditionally, work from our laboratory as well as from others abundance of surface receptor. The proliferative zone expandsshow that manipulation of the immune response within wild- and extends down throughout the gastric glands encompassingtype strains dramatically alters disease such that skewing an a wider area of cells, and suggesting to us that additional cellimmune response toward Th2 polarization protects the C57BL/6 populations may be involved in proliferation under these cir-host from Helicobacter induced atrophy and metaplasia [92]. cumstances. This increased proliferation results in increased cellConversely induction of a Th1 response in the Balb/C induces numbers and the potential for accumulation of genetic defectsatrophy, metaplasia and dysplasia [93] and converts this formerly and progression to cancer.resistant strain to a sensitive host. While mice tend to have polarized immune responses, 7. Metaplasiahumans can more accurately be described as having cytokinepatterns which fall somewhere on a continuum between these As described above, the marked changes in apoptosis andtwo “ideal” extremes making the designation of an immune proliferation rates associated with chronic Helicobacter infec-response as Th1 or Th2 somewhat artificial and simplistic. tion leads to marked changes alterations in the gastric mucosa,Progression to atrophy and cancer is so dependent on a Th1 and progression to a lesion known as gastric atrophy. Gastricimmune response in the mouse model; it was therefore natural atrophy has been defined as the loss of normal glandular com-to look for a link between these immune factors and human–host ponents and cell types (such as parietal and chief cells in thegenetic susceptibility. The first cytokine studied in detail was gastric fundus) and is typically associated with metaplasia. InIL-1␤, a pro-inflammatory cytokine shown to induce gastrin the Helicobacter felis (H. felis)-C57BL/6 mouse model, whenrelease, inhibit acid secretion, and promote apoptosis. Studies mice are infected for more than a few months, the degree ofby El-Omar looking at single nucleotide polymorphisms (SNPs) metaplasia becomes striking with a marked expansion of mucouswithin the IL-1␤ gene suggest that high-expressing IL-1␤ geno- metaplastic cells. The first clue to the nature of this metaplasiatypes increase the risk of developing both atrophy and gastric was provided by studies in 1998 that showed that this meta-cancer secondary to Helicobacter infection [94]. Further, a com- plastic lineage was characterized by expression of trefoil factorbination of IL-1␤, TNF-␣ and IL-10 SNPs which potentially family 2 (TFF2), also known as spasmolytic polypeptide (SP).result in a phenotype of elevated IL-1␤ and TNF-␣ and decreased Consequently, this lineage was named SPEM, for spasmolyticIL-10, confers a 50-fold increased risk of gastric cancer [95]. polypeptide-expressing metaplasia. This SPEM lineage demon-One mechanism of action may be to induce a hypochlorhydric strated morphology quite similar to that of either Brunner’s glandstate and atrophic response to Helicobacter infection. Addition- or the deep cells of the antral glands. The lineage was subse-ally, cytokine mediated cell signaling, either directly through quently identified in several other animal models, all of whichreceptor–ligand interaction, or via upregulation of growth mod- share the common feature of several parietal cell loss or oxynticulating signal cascades may possibly explain the deleterious atrophy. In the case of the H. felis-C57BL/6 mouse, the SPEMeffects of Th1 cytokines on gastric mucosal cell growth. Indeed, lineage appeared to progress to dysplasia followed by submu-cytokines prominent within the Th1 type response specifi- cosal and vascular invasion, suggesting that this lineage was incally IL-1␤, TNF-␣ and IFN-␥ upregulate the expression of fact the precursor to gastric adenocarcinoma.Fas Ag on gastric mucosal cells leading to alterations in cell Subsequent studies by Goldenring and colleagues led to thegrowth [96]. identification of the SPEM lineage in human specimens, partic- Imbalance of the apoptosis/proliferation ratio has been shown ularly in association with gastric cancer. Three studies of gastricin many systems to be a prominent feature in the progression cancer patients that were performed in the United States, Japan,from premalignant to malignant states thus offering a plausible and Iceland, came to the same conclusion, indicating that SPEMmechanism through which the cytokine milieu influences dis- shows an equal or greater association with gastric cancer thanease in the infected host. Normally the link between apoptosis did intestinal metaplasia. In most of the cancer groups, TFF2and proliferation is tightly regulated in order to achieve con- was found to be expressed in 35–50% of the dysplasia samples,trolled cell turnover and maintain tissue homeostasis. Apoptosis and occasionally in metastatic lesions, supporting the notionoccurs primarily in gastric pits, and proliferation is confined to that SPEM may be the precursor for gastric cancer. The phe-the upper neck region of the gastric isthmus. Both occur at low notype of SPEM resembles closely a lesion that has previouslylevels, with apoptosis balanced by the replacement of cells by been termed pseudopyloric metaplasia, and in fact this lesion
  7. 7. J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203 197has come to be recognized as present in every case in which 8. BMDC origin of gastric canceratrophic gastritis occurs. While TFF2 is expressed by mucous neck cells in the normal Chronic inflammation is central in the pathogenesis of gastricfundic glands and by mucous cells at the base of the antral glands, cancer, allowing us to use this type of tumor as a model in whichthe appearance and morphology of SPEM is quite different, rais- to test our theory that bone marrow-derived stem cells, as theing questions as to the origins of this lineage. In order to define ultimate uncommitted adult stem cell, represent the ideal candi-further the SPEM lineage, Nomura and colleagues undertook date for transformation. To do this, we used the well-describedstudies of SPEM related transcripts using laser capture microdis- C57BL/6 mouse model of Helicobacter induced gastric cancersection and microarray analysis. This study showed a relatively [99]. This model closely mimics human infection and cancerunique set of transcripts, including a number such as the non- formation. As in humans, gastric cancer in the mouse rarely iscoding RNA Xist, that are not normally expressed in the adult encountered in the absence of Helicobacter infection, and long-male animal. Xist, is a gene encoded on the X-chromosome that standing infection carries a significant risk of gastric cancer.plays a role in X-inactivation and expression has never been For our study, C57BL/6 mice were lethally irradiated andreported in male cells other than spermatogenic lineages, germ transplantated with gender-mismatched bone marrow fromline cell tumors, and early in embryonic development. mice expressing a non-mammalian beta-galactosidase enzymeFig. 2. Helicobacter induced gastric cancer is derived from BMDCs. (A) Experimental plan to detect BMDCs within gastric cancer. (B) C57BL/6 mice transplantedwith ROSA26 bone marrow, infected with H. felis for 8 weeks and stained with the X-gal reagent demonstrate donor-derived (blue-arrow) cells within the mucosa,but not within glands as a component of the epithelium. (C) After 20–30 weeks of infection, dysplasia develops which is composed of BMDCs (blue-large gland).Additionally, fibroblasts (left arrows) and epithelial cells (right arrow) are also derived from BMDCs within areas of dysplasia. (D) IHC for beta-galactosidase (brownintracytoplasmic staining) reveals BMDCs comprise entire gland units within areas of GIN (gastrointestinal intraepithelial neoplasia).
  8. 8. 198 J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203[C57BL/6JGtrosa26 (ROSA 26)], green fluorescent protein tory of disease; epithelial changes in our model progressed from[C57BL/6J-beta-actin-EGFP (GFP)], or with control marrow severe dysplasia (Fig. 2C), to intraepithelial neoplasia (Fig. 2D)from C57BL/6 liter mates (Fig. 2A). Mice were allowed to to more invasive adenocarcinoma with prolonged infection [100]recover, and were subsequently infected with H. felis. After (Fig. 3A). BMDC comprised entire metaplastic and dysplasticvarying lengths of infection time, BMDCs engraftment into the gland units, and all areas of neoplasia were bone marrow derived.gastric mucosa was evaluated by several independent methods.We evaluated enzyme activity using the X-gal reagent which 9. Stem cells in tumor stroma and tumor angiogenesisrenders all cells carrying the B-galactosidase enzyme blue,bacterial-specific B-galactosidase immunohistochemistry (IHC) Stromal cells comprise a large portion of the tumor mass;(Fig. 2B and C) and detection of LacZNeo fusion gene sequence indeed, up to 60–90% of the mass of some tumors (e.g. colonicby PCR within beta-galactosidase positive gastric glands which neoplasms) are made up of stromal cells (Fig. 3B and C), with ahad been isolated by laser capture microscopy in those mice large portion of these stromal cells derived from a bone marrowtransplanted with ROSA26 marrow. In mice transplanted with source [101,102]. While stromal cells are vital for the survivalgreen fluorescent protein (GFP), we detected GFP by specific and growth of the tumor, they themselves are not malignant.GFP-immunohistochemistry of tissue sections (Fig. 2C), and A large component of the stroma are myofibroblasts. Interest-FACS analysis of GFP positive cells from single cell prepara- ingly, myofibroblasts are found in conditions and environmentstions derived from the infected stomach. These GFP positive other than cancer [103], specifically in the purported stem cellcells were then confirmed to be cytokeratin positive, CD45 neg- niche of solid organs and found in increased number in chron-ative and contain a single X- and Y-chromosome. Additionally, ically inflamed tissues where they contribute to the productionX- and Y-chromosome fluorescent in situ hybridization (X and of growth factors and chemokines [104].Y-FISH) confirmed the presence of donor-derived cells as gastric The formation of new blood vessels within a tumor, tumormucosal cells [100]. angiogenesis, is vital for tumor growth and survival. Malignant We next tested if normal repair of the stomach required transformation and the continued growth of a malignant cellBMDCs, or if engraftment was related to longstanding inflam- require a fertile microenvironment. At least two of the cell typesmation and damage. To do this, we used cryoinjury or acetic acid within cancer previously thought to arise locally – myofibrob-induced gastric ulcers to induce acute ulceration which would lasts and endothelial cells – have now been shown to derive inheal completely upon removal of the offending agent. The area part from circulating bone marrow progenitors [105,106]. Tumorof ulceration was examined acutely, during healing, and after cells, inflammatory cells infiltrating the tumors and stromal cellshealing for evidence of BMDCs engraftment. Also, we selec- release factors responsible for the mobilization of bone marrow-tively, but reversibly ablated parietal cells, allowed repopulation derived endothelial progenitor cells and induce them to migrateto occur and evaluated for the presence of BMDCs within the to, and become incorporated into the developing vasculature ofhealed tissue. Neither acute ulceration nor selective parietal cell the tumor [106]. Cancer is no longer thought of as simply a nidusablation required BMDCs for repair [100] and neither condition of genetically transformed epithelial cells, nor can the local envi-was associated with any evidence of marrow engraftment as gas- ronment be regarded as the sole source of the diseased tissue.tric epithelium. The condition that did seem to be required for Tumor progression likely is regulated by a more complex set ofengraftment was long standing inflammation and inflammatory growth factors and collaboration with as yet unrecognized cellmediated damage to the epithelium, an environment strongly types.linked to the development of cancer in many settings. In theHelicobacter-gastric cancer mouse model, inflammation is an 10. Why not a gastric stem cell?early event, and appears most intense early in infection, witha plateau at approximately 8 weeks, after which the number As discussed earlier, tissue stem cells are an attractive can-of recoverable organisms gradually declines, and inflammation didate cell for the cancer stem cell. These peripheral stem cellsdecreases as the level of tissue damage and specialized cell loss replenish physiologic cell loss as well as cells lost due to injury.progresses. In our model, donor-derived inflammatory cells were They have an extended life span theoretically positioning themabundant during early infection (Fig. 2B, arrows), but we did not to accumulate the requisite genetic damage for transformation.see engraftment within the epithelium during this time of intense Also, these cells are able to modulate their growth and differ-inflammation. Rather engraftment was not apparent until after entiation in response to local environmental conditions with in20 weeks, suggesting tissue damage may be needed in addition the organ and to rely on cell–cell interactions to determine lin-to inflammation to drive engraftment. Engrafted BMDC were eage fate. Tissue stem cells possess the ability to temporarilyalways within metaplastic or dysplastic glands, and we did not bypassing normal growth control programs to allow prolifera-identify any BMDC differentiating as normal specialized gastric tion under conditions requiring tissue replacement and woundcells such as chief or parietal cells. Though slow in onset—once healing. This ability to proliferate under a broader range of con-engraftment began, the number of bone marrow-derived glands ditions, and within the setting of conflicting signaling may leadincreased substantially over the ensuing weeks suggesting a to the accumulation of mutations. Also, as apoptotic programsthreshold for recruitment had been reached. Helicobacter infec- are usually bypassed or suppressed during healing, cells whichtion causes gastric adenocarcinoma by 12–15 months in the would normally be deleted because of damage may be inappro-C57BL/6 mouse model [87]. In keeping with the natural his- priately retained. As the process of wound healing is usually
  9. 9. J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203 199Fig. 3. BMDCs contribute to various aspects of cancer initiation and growth. (A) BMDCs contribute to tumors directly. (B) BMDCs contribute to tumor growthas activated fibroblasts, myofibroblasts and endothelial progenitors. (C) Tumor angiogenesis. Tumor cells release a host of factors which promote cell cycling andincrease the motility of otherwise quiescent sessile VEGF receptor 2+ (VEGFR2+) endothelial, and VEGF receptor 1+ (VEGFR1+) hematopoetic stem/progenitorcells. Factors are released which also activate fibroblasts. Cells are mobilized to the peripheral circulation and ultimately incorporated into neovasculature of tumors.Growth factors, such as VEGF, bFGF, PDGF and MMPs are also produced by tissue-restricted fibroblasts and immune cells.
  10. 10. 200 J. Houghton et al. / Seminars in Cancer Biology 17 (2007) 191–203short lived, this is not usually a relevant issue. However, in tissues and/or may depend on the mechanism of injury induc-the setting of chronic injury and inflammation the unrelenting ing these events. Irrespective of the mechanism involved—bonestimulus to replicate combined with avoidance of apoptosis pre- marrow-derived cells have been shown to engraft and take ondisposes to the accumulation of transforming mutations. the function of cells within peripheral tissues. The question of The current evidence supports the tissue stem cell as a leading how the environment delivers homing signals, what these sig-candidate for the cancer stem cell however; there are several key nals are, how they are modulated by inflammation and injuryreasons to look further for the candidate cell. First, using cell pro- and most importantly, how these signals can be manipulated forliferation mapping and radiation regeneration/clonogenic assays therapeutic benefit remain to be addressed.the putative stem cell niche has been identified within the lumi-nal gastrointestinal tract. Unfortunately, there are not defined 12. Human studiesmarkers to date which identify this cell type, and its locationhas only been implied. Within the stomach, the stem cell is There have been few studies that have addressed the questionpurported to reside mid-crypt in the fundus, and basally in the of cellular origins of cancer in human patients. One study [115]antral glands [107]. These putative stem cells divide slowly, giv- has reported a case of skin cancer arising from donor cells in aing rise to daughter cells which proliferate at a much greater kidney transplant patient. Since kidneys are reportedly rich inrate and comprise the “BrdU positive” population which are mesenchymal stem cells, the putative BMDC subpopulation thatroutinely evaluated during studies of proliferation. Therefore, gives rise to gastric cancer, this report would be consistent withthe “stem cell zone” as commonly defined is marked by the our current model. While several studies in patients with stemhighest density of BrdU positive cells and contains both the cell transplants have not shown donor contribution to tumor cellstrue stem cell and the first few generations of daughter cells [116] the follow up has been short and the tumors mostly non-(transient amplifying cells) which are capable of division. We adenocarcinomas. Another recent letter examined the origins ofmust resolve the paradox that the compartment which houses breast cancer in five women who had gender-mismatched stemthe purported stem cell is also the compartment typically dam- cell transplants and found no donor contribution with followaged and depleted by potential carcinogens [108]. A common ups that were 1.5–10 years. However, one major limitation ofoutcome of chronic inflammation of many organs, including these types of studies is that most of these recent transplantsthe stomach, is atrophy and specialized cell loss. Atrophy and have been with CD34+ stem cells (i.e. HSCs, not MSCs). Givencell loss are the tangible effects of peripheral stem cell injury that data from our murine studies which suggests that the can-and malfunction—therefore, the very cell thought to be trans- cer stem cell is more likely of mesenchymal origin, one wouldformed is lost. Based on these data, we speculate an additional not expect that stem cell transplantations (SCT) using CD34+source of stem cells, specifically bone marrow-derived stem selection techniques to repopulate the recipient bone marrowcells, contribute to tissue repair and to the formation of cancer with multipotent MSCs. It is apparent that gender-mismatchedunder conditions of longstanding injury and inflammation. Bone transplants that do not employ whole bone marrow will not bemarrow-derived mesenchymal stem cells (MSCs) have several able to address at all the question of the bone marrow source ofunique properties which make them an attractive candidate cell adenocarcinoma in human patients, and that such studies willfor transformation. First mesenchymal cells from the marrow await the identification of more specific sets of markers. Indeed,have shown plasticity, having been recovered as differentiated given the unique nature of markers such as Xist, and its closecells from virtually every organ system studied [109]. Also, in association with BMDCs in our murine model of gastric cancer,vitro data suggest strongly that MSCs may be more mutagenic the expression of Xist in human gastric cancer would providethan other cell types, and may transform more easily [110,111]. support for the BMDCs model in humans.Also, studies suggest that MSCs may home to components ofthe inflammatory environment [112,113], offering a mechanism Referencesby which these cells may enter the tissue during infection andinflammation. Once in the tissue and exposed to the conflicting [1] Shimkin MB. Contrary to nature. Washington, DC: US Department ofgrowth signaling environment of inflammation, MSCs plasticity Health, Education and Welfare; 1977. [2] Rather LJ. The genesis of cancer: a study in the history of ideas. 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