Editorial

10.1586/14737140.7.5.609 © 2007 Future Drugs Ltd ISSN 1473-7140 609

Targeted TGF-β chemotherapies: friend or foe in treating human malignancies?‘Despite intense research efforts over the last decade by scientists in academic and industrial settings, complete success in targeting the TGF-β signaling system in human cancers has remained elusive.’

William P SchiemannDepartment of Pharmacology, MS-8303, University of Colorado Health Sciences Center, RC1 South Tower, Room L18–6110, 12801 East 17th Avenue, PO Box 6511, Aurora, CO 80045, USATel.: +1 303 724 1541Fax: +1 303 724 3663bill.schiemann@uchsc.edu

Expert Rev. Anticancer Ther. 7(5), 609–611 (2007)

Transforming growth factor-β paradoxTransforming growth factor (TGF)-β is a mul-tifunctional cytokine that plays essential rolesin regulating virtually all aspects of mammaliandevelopment and differentiation, and in main-taining mammalian tissue homeostasis [1,2].Indeed, the ubiquitous and multifunctionalnature of TGF-β is highlighted by the fact thatvirtually every cell in the metazoan body iscapable of both producing and responding tothis cytokine. Although TGF-β was identifiedoriginally via its stimulation of morphologicaltransformation and anchorage-independentgrowth in rat NRK-49 kidney fibroblasts, thiscytokine is now recognized as being a potenttumor suppressor that prevents the dysregu-lated growth and survival of cells derived fromepithelial, endothelial or hematopoietic line-ages [1,2]. The process of tumorigenesis and itsassortment of associated genetic and epigeneticevents enable newly malignant cells to evadethe cytostatic activities of TGF-β. As cancercells continue down the evolutionary pathtowards advanced malignancy, they ultimatelyacquire the ability to transform the cytostaticsignals produced by TGF-β into oncogenicactivities, including enhanced proliferation,invasion and metastasis. The ability of malig-nant cells to convert the biological actions ofTGF-β (i.e., tumor suppression) into patho-logical symptoms (i.e., tumor promotion) iscommonly referred to as the ‘TGF-β paradox’,which remains the most important and unan-swered question concerning physiologicalfunctions of this multifunctional cytokine.

Moreover, the schizophrenic nature exhibitedby TGF-β during tumorigenesis is notrestricted solely to the cancer cells themselves,but also occurs in their accompanying stromalcomponents, including fibroblasts, endo-thelial and infiltrating immune cells [1,2].Indeed, when activated by TGF-β, these vari-ous stromal components conspire to create atumor–host microenvironment that pro-motes the induction, selection and expansionof metastatic cells, thereby ensuring dissemi-nation of the disease beyond its tissue of ori-gin [1,2]. The consistent and repeated findingin nature of cancer cells that readily undergoinvasion and metastasis in response to TGF-βunderscores the importance of creating novelchemotherapeutics operant in targeting theoncogenic activities of TGF-β in developingand progressing human cancers.

Despite intense research efforts over the lastdecade by scientists in academic and industrialsettings, complete success in targeting theTGF-β signaling system in human cancers hasremained elusive. Indeed, the multifunctionalnature of TGF-β probably represents the great-est barrier to effectively targeting TGF-β, itsreceptors and their downstream effectors inhuman tumors, which must acquire six dis-tinct tumorigenic phenotypes in the course oftheir neoplastic journey. For instance, allcancer cells must develop the capacity to pro-liferate autonomously, ignore cytostatic sig-nals, resist apoptotic signals, become angio-genic, initiate tissue invasion and metastasis,and become immortal [3]. We and others have

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shown that TGF-β plays a prominent role in regulating, eitherdirectly or indirectly, the acquisition of each of these individualtraits by malignant cells [1,2,4,5]. Furthermore, the role of TGF-βin maintaining cell and tissue homeostasis necessitates thatextreme caution be exercised during the delivery of targetedTGF-β therapies. For example, pan-antagonism of TGF-βfunction during the infancy of tumorigenesis may in fact pro-mote cancer development by alleviating the cytostatic activitiesof TGF-β, not only in the malignant cells themselves [1,2], butalso in their stromal counterparts where the loss of TGF-βfunction promotes neoplastic development [6,7]. This caveat iscountered by the belief that adminis-tration of pan-TGF-β antagonists toadvanced-stage cancers will inhibitthe oncogenic activities of TGF-β,particularly its ability to inducetumor angiogenesis, invasion andmetastasis, and its ability to inhibithost immunosurveillance. Thus, the timing, context and dis-ease status initially encountered when deciding to launch tar-geted TGF-β treatment regimens will require critical informa-tion capable of identifying which cancer patients are potentiallyindicated or contraindicated for anti-TGF-β therapy.

Targeted transforming growth factor-β chemotherapiesAt present, targeted TGF-β chemotherapies come in two fla-vors, namely large- and small-molecule TGF-β inhibitors [8].Large-molecule inhibitors of TGF-β signaling include mono-clonal anti-TGF-β antibodies (e.g., GC1008), solubleTβR-II–Fc fusion proteins, decorin and soluble TβR-III, aswell as antisense TGF-β2 oligonucleotides (e.g., AP12009)[1,2,8]. In general, these molecules inhibit TGF-β signaling byneutralizing and/or sequestering TGF-β from its cell surfacereceptors or by limiting the production of TGF-β withintumor microenvironments. Other examples of large-moleculeTGF-β antagonists are cystatin C, which binds TβR-II andprevents its binding to TGF-β [9,10] and fetuin/α-2HS glyco-protein, which binds TGF-β and prevents its binding toTβR-II [11,12]. As a group, these molecules effectively antago-nize TGF-β signaling in a number of in vitro systems thatmodel key tumorigenic processes (e.g., epithelial–mesenchy-mal transition [EMT], migration and invasion), as well asreduce the growth and metastasis of murine 4T1 breast cancercells in mice [1,2]. Conversely, the growth of human MDA-MB-231 breast cancer cells in mice was enhanced by adminis-tration of neutralizing TGF-β antibody (e.g., human GC1008or mouse ID11), as was the progression of indolent colon ade-nomas to highly aggressive adenocarcinomas [1,2]. Thus, abro-gating TGF-β signaling within specific tumor microenviron-ments may in fact exacerbate disease development in amanner predicted by the TGF-β paradox. Despite theseapparent concerns, GC1008 has entered human clinical trialsto evaluate its effectiveness in treating patients with idiopathicpulmonary fibrosis, as well as those with metastatic skin andrenal cancers [1,2].

In contrast to the TGF-β neutralizing activity of large-mole-cule TGF-β antagonists, those of the small-molecule flavor arecomprised of compounds that bind competitively with varyingselectivities to the ATP-binding site of the TβR-I proteinkinase domain (e.g., LY580276, SB431542, A-83–01, orSD-208 and -093) [8]. As with the administration of large-molecule inhibitors, the use of small-molecule antagonists tomanipulate TGF-β signaling in cancer cells has producedmixed results. For instance, TβR-I antagonists inhibit the abil-ity of TGF-β to stimulate EMT and invasion in normal andmalignant cells [1,2,8], suggesting that physiological EMT (i.e.,

wound healing and tissue remode-ling) may be negatively impacted incancer patients treated with thesedrugs. In addition, while administra-tion of TβR-I antagonists toadvanced-stage cancers inhibitsoncogenic signaling by TGF-β, this

same treatment protocol actually enhances the malignancy ofearly stage cancers that remain sensitive to the cytostaticactions of TGF-β. These findings underlie the necessity ofdesigning and implementing rapid diagnostic tests capable ofdiscriminating those cancer patients most likely to benefitfrom targeted TGF-β therapies from those individuals mostlikely to be harmed by TGF-β antagonism. This point is med-ically relevant as cancer cells that have undergone oncogenicEMT often develop resistance to standard cancer chemothera-pies. Thus, administration of TβR-I antagonists in conjunc-tion with erlotinib, an epidermal growth factor receptor antag-onist, may afford new avenues to control the metastatic spreadof developing and progressing cancers. Along these lines, TβR-Iantagonists have recently been shown to inhibit the growthand metastasis of breast and pancreatic cancers implanted intomice. Interestingly, these pharmacological effects were notobserved in immunocompromised mice [13], suggesting thatTβR-I inhibitors play a prominent role in eliminating tumorsby bolstering host immunosurveillance. Despite many of theuncertainties associated with the use of targeted TGF-β thera-pies, this novel class of cancer chemotherapeutics remains anattractive and potentially powerful approach to control thedevelopment and spread of human malignancies.

Future directions in targeting the transforming growth factor-β paradoxGenerally speaking, the targeted TGF-β therapies discussedpreviously uniformly function as pan-TGF-β antagonists whoseactivities are subject to the phenomena underlying the TGF-βparadox. Although considerable progress in our understandingof the TGF-β paradox has been achieved in recent years, scienceand medicine still do not yet know precisely how carcinogenesisconverts the cellular response to TGF-β. What is known is thatcanonical Smad2/3/4 signaling plays a prominent role in medi-ating the cytostatic function of TGF-β, while inappropriate oramplified activation of noncanonical signaling by TGF-β(e.g., mitogen-activated protein kinases [MAPKs], AKT and

‘By continuing to unravel the mysteries that underlie the biology and pathology of TGF-β, it may one day be possible to selectively target the oncogenic activities of TGF-β.’

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nuclear factor [NF]-κB), together with altered Smad2/3 signal-ing inputs, contribute to oncogenic signaling by TGF-β [1,2,14].It therefore stands to reason that specific targeting of nonca-nonical pathways activated by TGF-β, as opposed to pan-antagonism of TGF-β signaling itself, may provide novel ave-nues to circumvent the TGF-β paradox and restore thetumor-suppressing function of TGF-β in human cancers. Werecently discovered a novel αvβ3 integrin–Src–phospho-Y284–TβR-II–Grb2–p38 MAPK signaling axis whose activa-tion mediates oncogenic signaling by TGF-β in normal andmalignant mammary epithelial cells [15,16]. Importantly, theability of TGF-β to stimulate the growth and pulmonarymetastasis of breast cancers in mice absolutely requires activa-tion of this oncogenic signaling complex [GALLIHER AJ & SCHIE-

MANN WP, UNPUBLISHED DATA]. We also uncovered a novelTAB1–TAK1–IKKβ–xIAP–NF-κB signaling axis that formsaberrantly in breast cancer cells, but not in their normal coun-terparts, and enables oncogenic signaling by TGF-β [NEIL JR &

SCHIEMANN WP, SUBMITTED]. Importantly, interdicting the abilityof TGF-β to activate either oncogenic signaling axis abrogatedthe tumor-promoting activities of TGF-β without affecting itscoupling to Smad2/3. The net effect of selective TGF-β antago-nism was a partial restoration of the cytostatic function of TGF-β in breast cancer cells, a result most likely arising from the factthat oncogenic signaling by TGF-β appears to be evolutionarily

and functionally redundant to that mediated by growth factorreceptors. Future studies clearly need to address the validity ofthis hypothesis; they also need to identify the molecular targetsactivated by these oncogenic signaling axes, as well as deter-mine their therapeutic potential as chemopreventive targets inalleviating cancer progression driven by TGF-β.

Parting thoughtsSolving and ultimately manipulating the TGF-β paradox toimprove the human condition is in many respects the ‘HolyGrail’ for TGF-β biologists and pharmacologists. By continu-ing to unravel the mysteries that underlie the biology andpathology of TGF-β, it may one day be possible to selectivelytarget the oncogenic activities of TGF-β and, consequently, to‘normalize’ malignant tissues in such a way that cancer itself isconverted from an acute, symptomatic and life-threatening dis-ease to one that is chronic, asymptomatic and manageablethrough the normal lifespan of affected individuals.

AcknowledgementsMembers of the Schiemann Laboratory are thanked for criticalcomments and reading of the manuscript. William P Schiemannis supported by grants from the National Institutes of Health(CA095519 and CA114039), the University of ColoradoCancer Center and the Cancer League of Colorado.

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Affiliation

• William P SchiemannDepartment of Pharmacology, MS-8303, University of Colorado Health Sciences Center, RC1 South Tower, Room L18–6110, 12801 East 17th Avenue, PO Box 6511, Aurora, CO 80045, USATel.: +1 303 724 1541Fax: +1 303 724 3663bill.schiemann@uchsc.edu