Cancer Spectrum: Narazaki et al., pp. = 294-295.

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Journal of the National Cancer Institute, Vol. 98, No. = 5, 294-295,=20 March 1, 2006
DOI: 10.1093/jnci/djj099

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=A9= The=20 Author 2006. Published by Oxford University Press.

EDITORIAL

Tumor Cell Populations Differ in Angiogenic Activity: A Model = System=20 for Spontaneous Angiogenic Switch Can Tell Us Why=20

Masashi Narazaki, Giovanna = Tosato=20

Affiliation of authors: Basic Research = Laboratory,=20 Center for Cancer Research, National Cancer Institute, Bethesda, = MD=20

Correspondence to: Giovanna Tosato, MD, = Bldg. 10,=20 12C205, 10 Center Dr., Bethesda, MD 20892 (e-mail: tosatog{at}mail.nih.gov ).

Aggressive, life-threatening cancers grow progressively = locally,⁼²⁰produce distant metastases, and are insensitive to = cytotoxic⁼²⁰and cytostatic drugs. A hallmark of progressive cancer = growth⁼²⁰is the subversion of the vascular supply in the whole area = that⁼²⁰is involved with tumor. In 1945, Glen Algire published in = this⁼²⁰Journal studies supporting the conclusion that "the rapid=20 growthof tumor explants is dependent on the = development of a=20 richvascular supply" (1).=20 We now know that many tumors are dependenton=20 neovascularization to sustain their expansion, that tumor⁼cells=20 themselves can produce proangiogenic factors, and that⁼certain=20 drugs targeting these factors can be effective anticancer⁼²⁰drugs.

Tumorigenesis represents a multistep process that leads to = the⁼²⁰accumulation of genetic alterations, including = gain-of-function⁼²⁰mutations in oncogenes and loss-of-function mutations in = tumor⁼²⁰suppressor genes (2).=20 One such step is known as the "angiogenicswitch," via = which=20 tumor cells acquire the ability to inducesprouting of = new=20 vessels from the surrounding quiescent vasculature⁼(3,4).=20 In some cases, the angiogenic switch has been linkedto = mutations of oncogenes or tumor suppressor genes. For = example,⁼²⁰the p53 tumor suppressor protein regulates the = antiangiogenic⁼²⁰factor thrombospondin 1, such that loss of p53 function, = which⁼²⁰is common to many tumor cells, reduces the levels of=20 thrombospondin1 (5).=20 In other examples, both activation of the ras oncogene⁼and loss=20 of the von Hippel=96Lindau tumor suppressor gene⁼promote the=20 expression of vascular endothelial growth factor⁼(VEGF),=20 resulting in increased endothelial cell growth and = angiogenesis⁼²⁰(6,7).=20 Unlike normal postnatal angiogenesis, which is observed⁼²⁰physiologically in the ovary and the endometrium or as = part⁼²⁰of wound healing in injured tissues=97in which the new = vessels⁼²⁰look normal and the process is self-limited and carefully=20 regulated=97incancer, the new vessels are often = structurally and=20 functionallyabnormal and the process does not stop, = due in=20 part to the defectivenature of the tumor vasculature, = which is=20 tortuous and leaky,leading to tissue hypoxia and = further=20 stimulation of angiogenesis(8).⁼²⁰

Autopsy studies have led to estimates that almost all = adults⁼²⁰between the ages of 50 and 70 years have small thyroid=20 carcinomas,only 0.1% of which are clinically apparent, = and=20 that 39% ofwomen between the ages of 40 and 50 years = have foci=20 of breastcancer, only 1% of which are clinically = apparent=20 (9).=20 All ofus may thus harbor some cancer cells in our = tissues,=20 particularlylater in life, and our fate may depend on = whether=20 such cellsturn into an aggressive cancer. It is = important to=20 know thesteps required for such small cancer foci to = grow into=20 lethalcancers and how to prevent the process. In this = issue of=20 theJournal, Naumov et al. (10)=20 have focused on the angiogenic switchthat is observed = when=20 small dormant cancers change into cancersthat grow = fast and=20 progress. They started from established breast⁼adenocarcinoma,=20 osteosarcoma, and glioblastoma cell lines, whichthey = injected=20 into severe combined immunodeficient (SCID) mice.⁼Tumors either=20 did not form or remained microscopic and harmlessfor = more than=20 100 days, sometimes as long as a year, but eventuallya = proportion of tumors started to grow progressively. The = authors⁼²⁰termed these growing tumors "angiogenic" because they = appeared⁼²⁰red and were vascularized, as opposed to the dormant = cancers,⁼²⁰which they termed "nonangiogenic" because they appeared = white⁼²⁰and poorly vascularized. Cells derived from the angiogenic=20 tumorswere reinjected into SCID mice. This time, the = tumors=20 grew muchmore rapidly in the mice and became palpable = by 21=20 days afterinjection. Thus, by using this method, the = authors=20 had selectedfrom three established cell lines = subpopulations=20 of tumor cellswith markedly different characteristics = with=20 respect to tumorformation in mice=97that is cells = forming=20 indolent tumors,at least indolent for quite some time, = or=20 cells forming rapidlygrowing tumors. The authors = looked for=20 differences that couldexplain these divergent = phenotypes. Both=20 cell types had similarproliferation rates in vitro, = but=20 compared with nonangiogenictumors, angiogenic tumors = produced=20 substantially greater amountsof the proangiogenic = factor basic=20 fibroblast growth factor (bFGF,also referred to as = fibroblast=20 growth factor 2, or FGF2) andsubstantially lower = levels of the=20 antiangiogenic factor thrombospondin1. Levels of VEGF = were=20 similarly elevated in nonangiogenic andangiogenic = breast=20 carcinoma and glioblastoma cell lines, butangiogenic=20 osteosarcoma cells produced substantially more VEGF⁼than=20 nonangiogenic osteosarcoma cells. Thus, in these examples,⁼the=20 ability of tumor cells to generate indolent or rapidly = growing⁼²⁰tumors correlated directly with levels of secreted=20 proangiogenicbFGF and indirectly with levels of = antiangiogenic=20 thrombospondin1.

Many activator and inhibitor proteins orchestrate = angiogenesis.⁼²⁰In addition to the FGF and VEGF protein families, other=20 proangiogenicfactors include platelet-derived growth = factors,=20 angiopoietins,placental-like growth factor, hepatocyte = growth=20 factor, transforminggrowth factors, stromal-derived = factor 1,=20 interleukin 8, andmonocyte chemoattractant protein 1 = (11).=20 In addition to thrombospondin1, negative regulators of = angiogenesis include the Notch ligandsDelta4 and = Jagged1=20 (12,13),=20 vasohibin (14),=20 endostatin (15),⁼²⁰angiostatin (16),=20 vasostatin (17),=20 and tumstatin (18).=20 Bloodvessels in different tissues may differ = phenotypically=20 (19),⁼²⁰and at least one tissue-specific proangiogenic factor has = been⁼²⁰identified (20),=20 suggesting the possibility of tissue-specific⁼regulation of=20 angiogenesis, including the angiogenic switch.Recent = studies=20 have explored the possible role in angiogenesisof axon = guidance receptors and their ligands, including semaphorins⁼and=20 plexin receptors, Slits and Robo receptors, ephrins and⁼Eph=20 receptors, and netrins-DCC/neogenin and Unc5 receptors (21=9623).⁼²⁰In some cases, the same factors that provide axons with=20 attractiveand repulsive cues have been found to = regulate=20 migration andsprouting in endothelial cells. For = example,=20 EphB4 can attractendothelial cells and promote = angiogenesis,=20 including tumorangiogenesis, through ephrinB2 reverse=20 signaling (24).=20 Tumorsexpressing Sema3F can repel endothelial cells in = vivo=20 and displayreduced vascularity; they are encapsulated = and=20 nonmetastatic(25).=20 It will be interesting to extend the observations by Naumov⁼et=20 al. to broadly examine expression of known regulators of⁼²⁰angiogenesis in nonangiogenic and angiogenic tumor cell=20 subsets.

Recent studies have proposed the existence of tumor stem = cells,⁼²⁰i.e., rare tumor cells within the bulk of proliferating = tumor⁼²⁰mass with self-renewing potential, quiescence of cell = cycling,⁼²⁰relative resistance to growth factors, and an ability to=20 differentiateinto diverse tumor components (26).=20 Such cells would play acritical role in sustaining = tumor=20 growth (27).=20 An importantquestion is whether tumor stem cells are=20 proangiogenic. Naumovet al. derived a tumor clone, A1, = from an=20 angiogenic breasttumor. Although it was derived from a = rapidly=20 growing tumor,this clone formed tumors in only 20% of = injected=20 mice and onlyfollowing a prolonged dormancy of about 1 = year.=20 Thus, the A1clone displayed some of the = characteristics=97the=20 abilityto self-renew, maintain relative quiescence and = differentiate=97oftumor stem cells. It is noteworthy = that the=20 dormant tumors fromthe A1 clone were nonangiogenic in = vivo for=20 a long time, giventhat other studies have suggested = that the=20 stem cell populationswithin breast cancer may promote=20 angiogenesis more vigorouslythan the non=96stem-cell = bulk of the=20 tumor cells (28).=20 Bydepriving tumor stem cells of the necessary = nutrients,=20 antiangiogenictherapies could be particularly = effective=20 against these cells,which might otherwise be = relatively=20 resistant to cytotoxic chemotherapy.

It is clear that the acquisition of an angiogenic = phenotype⁼²⁰is one of the rate-limiting steps for sustained growth of=20 certaintumors but is not itself sufficient for = manifestation=20 of a locallyinvasive and metastatic phenotype. Several = highly=20 vascular tumors,such as myomas uteri and angiomas, can = grow to=20 a relativelylarge size but do not usually become=20 life-threatening. Also,a proportion of cancers may not = require=20 an angiogenic switchand may rather derive sufficient = nutrients=20 by co-opting existinghost vessels (29).=20 Nonetheless, most tumor growth is cruciallydependent = on the=20 formation of a neovascular supply.

In 1971, Judah Folkman proposed the idea of using = inhibitors⁼²⁰of angiogenesis to treat cancer (30).=20 During the last 2 years,the U.S. Food and Drug = Administration=20 approved two such inhibitors.Bevacizumab (Avastin), a=20 humanized monoclonal antibody againstVEGF, was = approved for=20 the treatment of metastatic colorectalcancer in = combination=20 with chemotherapy, and sorafenib (Nexavar),a synthetic = inhibitor of several serine/threonine and receptor⁼tyrosine=20 kinases, including VEGF receptor 2, was approved for⁼the=20 treatment of advanced renal cell carcinoma. Many other drugs⁼²⁰that block angiogenesis are currently under development = (11).⁼²⁰Based on the observations made by Naumov et al. in this = issue⁼²⁰and by many others, particularly interesting approaches = would⁼²⁰be to prevent the angiogenic switch or to turn it off = before⁼²⁰tumors acquire a large blood supply. Understanding the=20 molecularbasis for the angiogenic switch and how to = regulate=20 it seemslike a very good start.

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