| "text": "This is an academic paper. This paper has corpus identifier PMC2532487\nAUTHORS: Y. Lynn Wang, Qi Miao\n\nABSTRACT:\nThe role of PPARγ in tumorigenesis is controversial. In this article, we review and analyze literature from the past decade that highlights the potential proneoplastic activity of PPARγ. We discuss the following five aspects of the nuclear hormone receptor and its agonists: (1) relative expression of PPARγ in human tumor versus normal tissues; (2) receptor-dependent proneoplastic effects; (3) impact of PPARγ and its agonists on tumors in animal models; (4) clinical trials of thiazolidinediones (TZDs) in human malignancies; (5) TZDs as chemopreventive agents in epidemiology studies. The focus is placed on the most relevant in vivo animal models and human data. In vitro cell line studies are included only when the effects are shown to be dependent on the PPARγ receptor.\n\nBODY:\n1. INTRODUCTIONPPARγ is a nuclear hormone receptor that requires\nligand binding for activation. In 1995, it\nwas discovered that PPARγ is the molecular target of thiazolidinediones\n(TZDs, [1]), a class of synthetic\ncompounds that are effective for the treatment of type 2 diabetes. This\ndiscovery spurred great interest in these agents, as well as in the receptor. Besides its function as an insulin sensitizer\nin diabetes, PPARγ was found to have a variety of roles in immunoregulation,\natherosclerosis, angiogenesis, and tumorigenesis.With regards to carcinogenesis,\ndebate continues as to whether PPARγ is pro- or antineoplastic, despite very active\nresearch over the past few years. At the cellular level, PPARγ was found to be involved in cancer cell\nsurvival/apoptosis, proliferation, and differentiation. While the apoptotic functions\nof PPARγ and its agonists are addressed by others in\nthis special issue, we will conduct a critical review of the literature that\nsuggests that PPARγ has a prosurvival activity. The review is mainly focused on data derived\nfrom in vivo models and/or human studies. In vitro cell line-based studies are\nincluded only when the effects are shown to be dependent on the PPARγ receptor.One important\nlesson learned from the past several years of research is that effects observed\nwith agonists of PPARγ are not necessarily intrinsic effects of the\nnuclear hormone receptor. In tumor cell survival, the proapoptotic activities of\nPPARγ agonists in various tumors act through both\nreceptor-dependent and receptor-independent mechanisms. When reviewing the\nliterature, we advise that the readers carefully consider the following to\ndistinguish drugs or TZDs versus receptor effects: (1) are high or low doses\nused in the studies? High or low doses\nshould be defined with respect to EC50 of glitazones in the PPARγ transactivation assays (Table 1) or plasma\nconcentrations that can be reached in humans (Table 2). Effects observed with\nhigh concentrations may not be relevant due to toxicities of certain TZDs, such\nas hepatotoxicity of troglitazone and potential cardiotoxicity of rosiglitazone\n(see below). (2) Are multiple pharmacological agents used? If a pharmacological\napproach is the only one used, claims of a receptor-dependent effect require\ndemonstration with agonists of different chemical structures, such as TZDs,\ntyrosine analogues, 15-Deoxy-Δ12,14-PGJ2 (15d-PGJ2),\nand so forth. Beware that 15d-PGJ2 possesses many PPARγ-independent activities, including inhibition\nof the NFκB pathway, that are known to have\nprosurvival and anti-inflammatory properties, as well as other effects [2–4]. (3) Are any antagonists\nincluded in the study? Do antagonists GW9662 or T0070907 block or reverse the\nobserved effects? (4) Are there any experiments in the study utilizing a genetic\napproach to confirm the pharmacological findings? Does the study involve cell lines or primary\ncells that contain or lack PPARγ, preferably in the same genetic background? For\nthose cell lines with endogenous PPARγ, is the siRNA, shRNA or dominant negative form\nof PPARγ used to reduce the levels of the receptor? Are\nspecific effects of the receptor diminished by such reduction? For readers'\nconvenience, these questions are summarized in Table 3.2. EXPRESSION OF PPARγ IN HUMAN TUMOR\nVERSUS NORMAL TISSUESIt is generally believed that expression of\na gene in a particular tissue suggests that the activity of the encoded protein\nis required for certain cellular functions of that tissue. In so far as cancers\nare concerned, the general rule is that oncogenes are overexpressed due to\ndysregulation, and tumor suppressor genes are underexpressed or absent due to\nmutations or deletions. In order to clarify the roles of the PPARγ receptor,\nit would be informative to review the expression levels of PPARγ in\ntumors with respect to their normal tissue counterparts. In this article, expression\ndata from tumor cell lines are not included.A review of the current literature on human\ncancers showed that expression levels of PPARγ mRNA and protein are generally higher in neoplastic\ntissues than their normal counterparts (summarized in Table 4). The most convincing data came from a large\nstudy of prostate cancer that included 156 patients with prostate cancer (PC),\n15 with less aggressive prostatic intraepithelial neoplasia (PIN), 20 with\nbenign prostatic hyperplasia, and 12 normal prostate tissues. In this study, a high level of PPARγ expression,\nby immunohistochemistry, is observed in PC and PIN cases in comparison to low\nor no expression in the benign hyperplasia and normal tissues. The results were\nconfirmed at the mRNA level with RT-PCR on a few cases from each category of\nthe malignant and benign conditions [13]. A large study of 126 renal cell carcinomas\nalso showed significantly more extensive and intensive PPARγ staining\nin tumor epithelium compared to the average staining levels seen in 20 normal\ntissues [14]. Similarly, in 22 patients with nonsmall\ncell lung carcinoma, higher levels of PPARγ are\nexpressed in tumor cells than in the surrounding normal tissue, as determined\nby immunohistochemical staining. In addition, higher expression levels in tumor\ncells are confirmed by Western blotting hybridization, using homogenized tissue\nsamples [15]. In hepatocellular carcinoma, immunostaining\nalso demonstrates that PPARγ is\noverexpressed in all of 20 carcinoma tissues but not in normal hepatocytes [16]. For squamous cell carcinoma, 20 cases of\nprimary tumor and six cases of lymph node metastasis were demonstrated to have\nincreased PPARγ protein\nexpression compared to normal tongue tissue [17]. Infiltrating adenocarcinoma of the breast\nalso expresses higher nuclear staining of PPARγ compared\nto normal ductal epithelial cells by immunohistochemical analysis. However,\nonly one of the three cases was shown [18]. For papillary thyroid carcinoma, six\npatients were studied to determine PPARγ mRNA\nexpression using reverse transcription PCR. The message was found in three of\nsix tumor tissues while the corresponding normal tissues do not express PPARγ [19].Follicular thyroid carcinoma, a less common\nhistological subtype of thyroid cancer, is characterized by a chromosomal\ntranslocation t(2;3) that results in a fusion between paired box gene 8 on\nchromosome 2 and PPARγ on\nchromosome 3 (PAX8-PPARγ). The fusion protein was initially thought to\nfunction as a dominant-negative inhibitor of the wild-type PPARγ protein\n[28]. However, a recent microarray study revealed\nthat (1) PPARγ transcript\nlevels in all seven cases of PAX8-PPARγ-containing\nfollicular carcinomas are more than 10-fold higher than normal thyroid tissues,\nas determined by both microarray and quantitative RT-PCR analyses; (2) the\nexpression profile of the fusion-positive follicular carcinomas shows induction\nof genes that are involved in fatty acid, amino acid, and glucose metabolic\npathways. Interestingly, many of the upregulated genes are known\ntranscriptional targets of the wild-type receptor, suggesting that the PAX8-PPARγ\nfusion protein functions similarly to wild-type PPARγ, rather\nthan antagonizing its activity. (3) Using cell lines transfected with PPARγ or the\nfusion protein, it is shown that expression of some genes, including angiogenic\nfactors PGF and ANGPTL4, is specifically upregulated by the fusion protein, particularly\nin the absence of ligand, indicating that the fusion protein is constitutively active.\nTaken together, these experimental data suggest that the translocation enhances\nthe function of PPARγ in a way\nthat contributes to the development or progression of follicular carcinoma of the\nthyroid [29].Upregulation of PPARγ has\nbeen demonstrated during tumor progression. Mueller et al. have found\nsignificant PPARγ staining\nin six cases of metastatic breast adenocarcinoma. In cell lines established\nfrom the primary and metastatic tumors of one of these patients, significantly higher\namounts of PPARγ transcript\nare shown in the cell line derived from the metastatic tumor [20]. In ovarian cancer, intensity and location\nof PPARγ immunostaining\nwere examined in 28 carcinoma cases along with 28 normal, benign or borderline cases.\nTwenty six of 28 carcinomas showed strongly positive PPARγ staining\ncompared to 2 weak-staining cases in the control group. Moreover, it is noted\nthat PPARγ staining\nwas predominantly nuclear in grade 2 or 3 tumors, as compared to a predominantly\ncytoplasmic staining pattern in grade 1 tumors [21]. Similar findings were made in transitional\ncell carcinoma of urinary bladder. Whereas no significant PPARγ immunoreactivity\nwas observed in 20 normal tissues, elevated PPARγ was\nfound in 168 tumors. Furthermore, the intensity of staining increased as the\nhistological grade increased from G1 to G3 and the tumor stage increased from\nearly (pT1 or lower) to advanced (stage 2 or higher) [22].A recent large study of 129 cases of\npancreatic ductal adenocarcinoma convincingly showed by array-based gene\nprofiling that expression of PPARγ in the\ntumor cells is ~7 fold higher than that in the normal ductal epithelia. This\nfinding was confirmed with immunohistochemical analysis of the tissue sections.\nNormal ductal epithelia showed insignificant staining for PPARγ. An\nearly lesion, intraepithelial neoplasia showed occasional PPARγ expression\nwhereas more than 70% of invasive pancreatic carcinoma demonstrated weak to\nstrong expression. Statistical analysis indeed revealed that expression of PPARγ correlates\nwith high tumor stage and higher tumor histological grade. More strikingly,\nexpression of PPARγ in pancreatic\ncancer is shown, by multivariant survival analysis, to be a significant\nprognostic indicator for shortened patient survival [23].In parallel\nto the above literature, levels of PPARγ mRNA\nfound in several well- or poorly-differentiated colorectal adenocarcinomas,\nwere similar to normal tissues [24]. Another group also found that the PPARγ immunostaining\nin well-, moderately-, or poorly-differentiated gastric adenocarcinomas is\ncomparable to that in noncancerous tissue adjacent to the tumor [25]. In liposarcomas, PPARγ\ntranscript levels are similar to that of the adipose tissue [26]. In adrenal glands, there is, again, no significant difference in mRNA\nexpression among cases of carcinoma, adenoma, and normal tissues [27]. Notably, at the time of composition of\nthis manuscript, we have not yet found any reports stating that PPARγ expression\nis downregulated or absent in human tumor versus normal tissues (Table 4).The next\nquestion is whether or not the PPARγ\nexpressed in tumor tissues is functional. Are ligands of PPARγ\npresent in the tumor tissues? A thorough and up to date literature search yielded\nfew results. The English abstract of a\nstudy published in a foreign language stated that there was no significant\ndifference in 15d-PGJ2 concentration between gastric cancer tissues\nand controls [30].\nAn earlier study showed that 15d-PGJ2 promotes the proliferation of HCA-7, a cyclooxygenase 2 (COX-2)-containing\ncolon cancer cell line at nanomolar concentrations. Further characterization by HPLC and mass\nspectrometry identified PGJ2, a chemical precursor of 15d-PGJ2 in the culture medium of HCA-7 cells [31]. COX-2 is a key enzyme in the\nbiochemical pathway that leads to the formation of cyclopentenone\nprostaglandins including 15d-PGJ2.\nOverexpression of COX-2 has been documented in many cancer types and contributes\nto tumor growth [32]. Overall, these few and somewhat circumstantial evidences\nsuggest that 15d-PGJ2 might be present in the tumor tissues.Does PPARγ lose\nor gain abnormal functions through mutations other than PAX8-PPARγ\ntranslocation? A large survey of human tumor samples and cancer cell lines does\nnot support such a notion. The exon 3 and 5 mutations, once reported in\nsporadic colon cancers [33], were not present in nearly 400 cell lines\nand primary tumor samples including lung, breast, prostate, colon cancers, and\nleukemias [34].Taken\ntogether, several lines of evidence regarding PPARγ expression\nsuggest a positive contributive role of the receptor in the development,\nmaintenance, or progression of human malignancies: (1) PPARγ is\noverexpressed in the vast majority of cancers. (2) In several types of cancer, PPARγ expression\nis further increased during tumor progression. (3) The oncogenic fusion PAX8-PPARγ results\nin PPARγ overexpression\nand upregulation of a similar profile of transcriptional targets as the\nwild-type protein. (4) Expression of PPARγ in\npancreatic cancer is associated with shorter survival.3. RECEPTOR-DEPENDENT PRONEOPLASTIC\nEFFECTS OF PPARγ\nIs there also\ncellular-level evidence suggesting that PPARγ promotes tumors? Most studies, especially\nthose employing high doses of TZDs, suggest that PPARγ agonists have antitumor activities through inhibition\nof cell proliferation or induction of apoptosis or differentiation. However, receptor-independent pathways are\ninvolved in most of the cases (reviewed elsewhere in this special issue). Then what does the receptor by itself do in\ntumors?Schaefer et al. showed that inhibition of PPARγ induces apoptosis of hepatocellular carcinoma\ncells (HCCs) by preventing their adhesion to the extracellular matrix,\nsuggesting that the activity of PPARγ is required for HCC cells to adhere and\nsurvive [16]. In that study, those\nparticular effects were shown to be receptor-dependent. Loss of cell adhesion\nrequires almost complete loss of PPARγ activity achieved by either PPARγ-targeting siRNA or PPARγ inhibitor T0070907. In addition, T0070907\ncauses cell death at concentrations far lower than those needed for PPARγ agonists rosiglitazone and troglitazone.\nTogether, the data suggest that PPARγ functions to promote tumor cell adhesion and\nsurvival in HCC cells. In line with this notion, the promoter region of\nhepatocyte growth factor contains a functional PPAR response element (PPRE) that\nmediates its transcriptional upregulation by PPARγ.\nThe growth factor plays an essential role in liver growth during embryonic\ndevelopment, as well as in maintenance and renewal of cells in various organs including liver, lung, and kidney, in\nadulthood [35].Our laboratory studied\nhuman anaplastic large T-cell lymphomas, a common form of large cell lymphoma\nin the pediatric population. We first demonstrated with immunohistochemical\nstaining that PPARγ is expressed in the malignant cells of the lymphoma\ntissues [36]. We then tested the effect of\nPPARγ activation in cell lines established from\npatients with this lymphoma. A pair of cell lines, Karpas 299 and SUP-M2 that, respectively,\ncontain and lack endogenous PPARγ were selected to address the receptor-dependency\nissue. Additionally, only low ligand concentrations were used, following\ninitial dose titration, to minimize any off-target effects. Using this system,\nwe have found that low doses of PPARγ agonists do not affect cell survival under\nnormal conditions. When cell death was induced by nutrient deprivation through\nserum withdrawal, activation of the receptor with low doses of rosiglitazone\n(0.5–2 μM) attenuated cell death, as compared to drug\nvehicle-treated cells. This result was reproducible with low doses of GW7845\n(0.5–2 μM) and 15d-PGJ2(0.5–1 μM). The effect occurred only in PPARγ-containing Karpas 299 cells but not in PPARγ-lacking SUP-M2 cells. Moreover, reducing PPARγ in Karpas 299 cells with siRNA diminished the\nprosurvival effect of the receptor. Furthermore, we showed that the prosurvival\neffect is mediated through PPARγ-dependent cellular metabolic changes,\nincluding increased cellular ATP levels, stabilized mitochondrial membrane\npotential, and reduced reactive oxygen species (ROS) production that each favor\ncell survival. PPARγ does so through coordinated regulation of the expression\nof ROS metabolic enzymes, including the p67 subunit of NADPH oxidase, uncoupling\nprotein 2 (UCP2), and manganese superoxide dismutase (Mn-SOD) at both mRNA and\nprotein levels that lead to ROS limitation. Lastly, we showed that stable\ntransfection of PPARγ into SUP-M2 cells not only improved cell\nsurvival, but also suppressed ROS accumulation during serum starvation. These\ngenetic manipulations have provided definitive evidence that PPARγ promotes lymphoma cell survival under\nconditions of nutrient deprivation.Our group has also\nmade similar findings in a murine cellular model [37, 38]. FL5.12 is a murine lymphocytic\ncell line that requires interleukin-3 (IL-3) for survival and proliferation. This cell\nline has been extensively used to characterize tumor cell metabolism [39]. FL5.12 cells express little\nPPARγ, but are killed by high concentrations of PPARγ agonists, 15d-PGJ2 (≥10 μM) and ciglitazone (≥80 μM). In an FL5.12 cell line stably-transfected\nwith PPARγ, low doses of PPARγ agonist do not affect cell viability under\nnormal conditions. However, when cells are induced to die by IL-3 withdrawal,\nlow doses of ciglitazone (10 μM) and rosiglitazone (0.05–2 μM) improved survival in only PPARγ-containing cells. Improved cell survival is\nalso accompanied by stabilized mitochondria and reduced ROS. Moreover, ATP\nproduction is required for PPARγ to exert its prosurvival effect. In this\nsystem, expression of a different panel of ROS metabolic enzymes including\ncatalase, and Cu/Zn-SOD are\ninvolved in reduction of the cellular levels of ROS. Functional PPRE sequences were\nshown to be present in the promoter regions of these two genes, suggesting that\nthe upregulation of their expression could be directly regulated by PPARγ [40–42]. Taken together, data from\nboth human and murine cell line studies suggest that PPARγ promotes tumor cell survival under conditions\nof nutrient/growth factor deprivation, and that the effect is not limited to a\nparticular system. The mechanism by which PPARγ increases cell survival is diagrammed in\nFigure 1 (Also see below).In support of the\nprosurvival activity of PPARγ in T-cell malignancies, Ferreira-Silva et al. very\nrecently showed that RNAi-mediated silencing of PPARγ in Jurkat T-cells caused increased DNA\nfragmentation and apoptosis as well as G2/M cell cycle arrest, arguing that the\nreceptor, proper, promotes the viability of the tumor cells [43].In parallel to\nthese findings in tumors, the prosurvival activity of PPARγ has been well documented in certain nonneoplastic\npathological conditions, especially ischemia-reperfusion injury in\nnutrient-sensitive tissues such as brain, heart and kidney [44–51]. Irreversible damage that results from\nprolonged ischemia causes stroke, and myocardial and kidney infarction. At the cellular\nlevel, cell death occurs as a result of nutrient deprivation and inflammatory\nresponses that involve the actions of proinflammatory cytokines, chemokines and\ntranscriptional factors. In addition,\nincreased production of ROS plays an important role in causing damage to macromolecules\nand eventual cell death [52]. A recent study using a rat\nmodel of cerebral focal ischemia has shown that expression of PPARγ mRNA and protein is upregulated in the areas\nadjacent to infarct caused by middle cerebral artery occlusion [46]. Administration of glitazones\nprior to, at the time of, or shortly after ischemia induction causes an\nincrease in DNA binding of the receptor. This is accompanied by a decrease in the\nexpression of a number of inflammatory genes, along with an increase in the\nexpression of antioxidant enzymes including catalase and Cu/Zn-SOD [44–47]. Consequently, these changes\nlead to limited cell demise, which eventually results in significantly reduced infarct\nsize. This process apparently works through a PPARγ-dependent mechanism, as GW9662 can block these\neffects of TZDs in animals [47]. Another PPARγ antagonist, T0070907, even increases the infarction\nsize, both in the presence and absence of PPARγ ligands [46].In light of both\nthese findings and the overexpression of PPARγ in many cancers, it is reasonable to\nhypothesize that the function of PPARγ in cancer is to confer a survival advantage\nupon the malignant cells, allowing them to survive in an adverse environment.\nAs a result of fast growth, the center of a three dimensional tumor mass is\noften deprived of oxygen, growth factors, glucose, and other nutrients due to\nexcessive demand and insufficient vascularization. However, cancer cells\npossess remarkable tolerance and are able to survive despite the adverse\nconditions [53, 54]. Besides increasing\nangiogenesis, increasing PPARγ might be another mechanism that allows tumor cells\nto enhance their survival under these unfavorable conditions (Figure 1).4. IMPACT OF PPARγ AND ITS AGONISTS ON\nANIMAL TUMOR MODELSAnimal models\nwere employed to examine the role of PPARγ in tumors. These systems can be categorized by\nhow the tumor models are generated and by how the dose/activity of PPARγ is altered. With respect to the former, tumors\ncan be generated with xenografts, carcinogens, or genetic manipulations. Watch\nfor spontaneous tumor formation in certain PPARγ genetic backgrounds has also been conducted. With\nrespect to the dose/activity of PPARγ, it can be altered using PPARγ agonists including TZDs or GW7845, or genetic manipulations\nincluding hemizygosity or tissue-specific overexpression or deletion of PPARγ. Results differ drastically between different\nmodel systems, even for the same types of cancer (Tables 5 and 6). This\nreview focuses on models that are more relevant to human cancers. As such, animal\nstudies involving TZD treatment of xenografted tumors are not discussed here.4.1. Colon cancer\nApc+/Min mice possess a\nnonsense mutation in one copy of the adenomatous polyposis coli (APC) gene\nwhich truncates the protein at amino acid 850. Loss-of-function mutations in\nthe APC gene are common in human familial adenomatous polyposis and can\nbe found in sporadic colon cancers as well. Using this model, which is highly relevant\nto human colon cancers, one study showed an increase in tumor number and size, as\nwell as worse histological grade in mice treated with troglitazone or\nrosiglitazone. This is associated with a rosiglitazone-induced increase in the β-catenin protein level in the colon tissues [55]. Another study [56], which also used Apc+/Min mice, reported an\nincrease in the number of colon polyps in troglitazone-treated mice, but\nreported no significant difference in tumor size or histology, which may be\nrelated to the shorter TZD treatments used in this study (5 weeks as compared\nto 8 weeks in the first study). Similar findings were made in Apc\n+/1638N:Mlh1\n+/−\ndouble mutant mice. In these mice, one copy of the APC gene is\ntruncated at amino acid position 1638 and one of the two alleles of the DNA\nrepair enzyme Mlh1 is absent. In the double mutant mice, troglitazone treatment\nsignificantly increased the number of mice that developed large intestine tumors\n[58]. In contrast to these reports, another\nstudy used Apc\n+/1638N mice crossed with hemizygous PPARγ mice.\nBecause homozygous deletion of PPARγ is\nembryonic-lethal, studies examining the dose effect of the gene employed either\na hemizygous Pparγ+/− \nmouse strain or a conditional knock-out strategy. No differences in\nsurvival, number of colonic tumors or β-catenin expression levels were observed\nbetween mice of Apc\n+/1638N :Ppar\nγ\n+/−\nand Apc\n+/1638N :Ppar\nγ\n+/+\nlittermates [57]. Therefore, in colon cancer induced by \nAPC mutations, it appears that activation of PPARγ by TZDs\npromotes tumor formation, while reduction of PPARγ gene\ndosage has little effect on tumor formation.In stark contrast to the APC genetic\ntumor models, carcinogen-generated colon cancer models seem to yield opposite\nresults. In the study that evaluated PPARγ haploinsufficiency\nin an Apc\n+/1638N\nbackground, the investigators also\ndetermined the effect of Pparγ+/− in azoxymethane-mediated colon cancer. Compared to the Pparγ+/+ mice, a greater number of haploinsufficient mice developed tumors in\nthe colon. The tumor-bearing Pparγ+/− mice also had a greater number of tumors in them that led to\nsignificantly decreased survival. In another study, mice with azoxymethane-mediated\ncolon cancer were treated with troglitazone, pioglitazone, or rosiglitazone.\nThis resulted in reduced incidence, number, and size of colorectal tumor [59]. Taken together, these data suggest that PPARγ suppress\nazoxymethane-induced colon carcinogenesis.What would happen in normal mice? Spontaneous\ncolon tumor development was evaluated in normal mice administered with\ntroglitazone [58]. All nine mice fed with troglitazone\ndeveloped tumors in the large intestine, in contrast to none of the 10 mice in\nthe control group. An earlier study did not find any tumors in 17\ntroglitazone-fed normal mice, possibly due to the short duration of feeding (5\nweeks in [56] versus 6 months in [58]).4.2. Mammary gland tumorsThe mammary gland tumor is another\nrelatively well-studied tumor in animals. Similar to colon carcinogenesis, data\non PPARγ's\nrole in mammary gland carcinogensis suggest a wide range of effect depending on\nthe tumor models (Tables 5 and 6). Some studies indicate no effect, while\nothers suggest that it has a tumor promoting role, while others yet suggest a tumor\nsuppressing role. A murine genetic model supports a tumor-promoting role [60]. In this model, the mammary gland tumor is\ninduced by mammary gland-specific expression of polyoma middle T antigen\n(MMTV-PyV). Mammary gland specific constitutive expression of PPARγ\n(MMTV-VpPPARγ) did\nnot yield tumor development. However, when crossed with the MMTV-PyV mice, the\ndouble mutant progeny developed more mammary gland tumors sooner than MMTV-PyV\nmice. The increased tumor burden eventually led to shorter survival.\nInterestingly, hemizygosity of PPARγ in\nthe MMTV-PyV background did not change the time course of tumor development. Exacerbation\nof tumor formation by PPARγ was\nascribed to increased Wnt-β catenin signaling as demonstrated by zebrafish\ndevelopmental models.In contrast to this genetic model,\nchemically induced mammary gland tumors were inhibited by PPARγ agonists.\nBoth TZDs and GW7845, a tyrosine analog, have been shown to exhibit antitumor\neffects. An early study using nitrosomethylurea (MNU) to induce mammary\ncarcinogenesis showed that GW7845 reduced the incidence, number of tumors \nper animal,\nand average weight of tumor at autopsy following a two-month administration of\nthe drug to rats [61]. In 7,12-dimethylbenzanthracene\n(DMBA)-mediated mouse carcinogenesis model, the animals develop multiple types\nof tumor, including mammary ductal papilloma and adenocarcinoma. Incidence of\nmammary gland tumor was significantly higher in Pparγ+/− mice than in Pparγ+/+ mice. The hemizygous mice\nalso had increased number of tumors and a lower survival rate [62].Spontaneous\ntumor formation was also examined in Pparγ+/− mice. Dose reduction of PPARγ does not make animals prone to increased\ncarcinogenesis [62]. In concordance with this\nfinding, the specific deletion of PPARγ in mouse mammary epithelia failed to induce\nmammary tumors in 20 mice observed for 12 months [63].4.3. Other cancersIn a murine prostate\ncancer model, generated using tissue-specific SV40 T antigen, reduced Pparγ+/− had no effects on tumor\nincidence, latency, size, histopathology, or disease progression [64]. However, in a murine follicular\nthyroid cancer model containing a dominant-negative mutant form of thyroid\nhormone receptor β (TRβPV/PV), loss of one PPARγ allele led to increased weight of\ntumor-bearing thyroid gland, increased lung metastasis, and shortened survival.\nIn addition, rosiglitazone treatment of TRβPV/PV mice reduced\nthyroid weight, and tumor progression [65], suggesting a\ntumor-suppressing role for PPARγ. Lastly, in gastric carcinoma, induced with\nMNU, PPARγ haploinsufficient mice had increased tumor\nincidence and shorter survival. Troglitazone treatment significantly reduced\ntumor incidence in mice with wild-type PPARγ background [66].In summary, results\nfrom animal studies regarding the role of PPARγ are conflicting and difficult to assess. For\nthe purpose of clarification, we attempted to analyze the published data\naccording to the cancer types, tumor induction models, PPARγ activation/reduction methods, and tumor\ncharacteristics (Tables 5 and 6). Our extensive analysis revealed no\nclear pattern. However, some trends have been noted: (1) in multiple types of carcinogen-induced tumor (Table 5, light grey shaded rows), PPARγ seems\nto have a tumor-suppressing function. This appears to be independent of how PPARγ is\nactivated or reduced, whereas in genetic tumor models (Table 5, un-shaded rows), the receptor exhibited all possible different effects. As to spontaneous\ntumors (Table 5, dark grey shaded rows), long-term use of troglitazone\nincreased tumor formation, whereas PPARγ reduction\nhad no effect; (2) a reduction of PPARγ dose\nby itself (Table 6, light grey shaded rows) is insufficient to induce spontaneous\ntumor formation, but in existing tumors, it either exacerbates tumor formation\nor have no effect at all; (3)\nTZDs (Table 6, un-shaded rows), in most cases, inhibits tumor\nformation with a rare exception of Apc+/Min mice.The activity of the Wnt/β-catenin signaling pathway might account for\nthese seemingly discrepant results, as tumor models generated by APC mutation\nor polyoma middle T antigen all involve overly active Wnt/β-catenin signaling. TZDs are shown to induce β-catenin in colon [55]. Paradoxically, reduction of PPARγ (Pparγ\n+/−) also increases β-catenin expression in colon [57]. The appropriate activation of PPARγ signaling\nmight also be important. Ligand-independent constitutive activation of PPARγ is\ninvolved in the development of mammary gland tumors [60] as well as in the action of PAX8-PPARγ in\nfollicular thyroid carcinoma [29].5. CLINICAL TRIALS OF TZDs IN\nHUMAN MALIGNANCIESAs discussed above, TZDs have been shown in many\npreclinical studies to possess antitumor effects that have prompted several\nearly-phase clinical studies to evaluate their efficacies in various types of\ncancers. In this review, we analyze these studies both in terms of clinical\nresponses and biological responses, focusing on recently published studies that\ninclude more than 10 patients (Table 7). A phase II clinical trial of rosiglitazone in 12\npatients with liposarcoma was recently conducted. Eight of 12 patients were\nfully evaluated for up to 16 months. As to clinical response, all patients\nprogressed while on treatment with a mean time-to-progression of 5.5 months.\nHistological appearance of repeated biopsy materials did not show any signs of\ntumor differentiation. In one of the 8 patients, PPARγ and fatty acid binding protein (FABP) were\ninduced after 12-week rosiglitazone therapy, but disease in this patient\nprogressed similarly to the others [68]. Ten patients with thyroid\ncancers were treated with rosiglitazone. Among them, 4 had partial response, 2\nhad stable disease, and the remaining 4 progressed. No correlation was found\nbetween the clinical response and levels of PPARγ mRNA and protein in these patients. PAX8-PPARγ status was not assessed [69]. An early study evaluated\nefficacy of troglitazone in 25 patients with metastatic colorectal carcinoma.\nAll 25 patients progressed with a median time-to-progression of 1.6 months and\na median survival time of 3.9 months [70].In breast cancer, data from two human trials have\nbeen published. An early trial on 22 women with refractory breast cancer showed\nno objective response to troglitazone in 18 of the 21 evaluable patients at 8\nweeks after treatment. The therapy was terminated in 16 patients due to\nprogression of their tumors. At 8 weeks, only three patients had stable\ndisease. All patients were evaluated for serum tumor markers, CEA and CA27.29,\nwhich showed increased levels within 8 weeks of treatment. Expression of PPARγ was not determined in the study [71]. A short-term pilot trial of\nrosiglitazone in 38 women with early stage breast cancer was conducted.\nClinical response was not assessed in this short-term (<6 week) study.\nBiological response, as assessed by Ki-67 staining on biopsy tissues before and\nafter treatment, was not detected in treated patients, either. Decreased\ninsulin levels and increased insulin sensitivity were noted in these patients,\nsuggesting that the rosiglitazone did affect metabolism as expected [72].An early phase II trial of troglitazone in 41\npatients with metastatic prostate cancer showed a decrease in levels of\nprostate-specific antigen (PSA) in 20% of patients enrolled in the study.\nProlonged stabilization of PSA was seen in 39% of patients [73]. However, these encouraging\nresults were not reproduced in a large double-blind, randomized, placebo-controlled\ntrial of rosiglitazone in 106 patients with recurrent prostate cancer [74]. The time-to-disease-progression\nwas not significantly different between the rosiglitazone and placebo groups.\nMoreover, the PSA doubling time, a predictor of clinical recurrence, was also\nnot prolonged by the treatment. Taken together, TZDs\nappear to show little benefit, both in terms of clinical response and\nbiological response, in treating various types of human cancers despite\npromising results from preclinical animal studies. It is worth noting that most\nof the studies use low doses of TZDs which are sufficient to activate PPARγ and control diabetes. It remains possible that\nhigher doses, even via receptor-independent pathways, would be beneficial for\ncancer patients. However, one should keep in mind that TZDs are not a class of\ndrugs without dose-limiting toxicities. Troglitazone was withdrawn from the\nmarket by the FDA in 2002 due to liver toxicity. Most recently, increased\ncardiovascular risk has been associated with rosiglitazone in the diabetic\npatient population [75, 76] which has prompted the FDA to\nissue label warnings.6. TZDs AS CHEMOPREVENTIVE AGENTS IN\nEPIDEMIOLOGY STUDIESThe clinical\ntrials discussed above suggest that TZDs have questionable efficacy as\nchemotherapeutic agents in patients who already have cancers. Do they have the\npotential to act as chemopreventive agents? Recently, a large epidemiologic\nstudy, involving a population of 87,678 veteran men with diabetes, attempted to\nanswer that question [77]. In this retrospective study,\nincidence of lung, prostate, and colon cancer in TZD users was compared to\nincidence in non-TZD users and risk of cancer development was analyzed. Only\npatients who obtained a cancer diagnosis after the date of TZD initiation were\nincluded. TZD usage significantly reduced risk of lung cancer by 33%. It also\nreduced risk of colon and prostate cancer, though without statistical\nsignificance. Interestingly, although the risk of prostate cancer is not significantly\ninfluenced by TZDs in the entire population, when examining distinct populations,\nTZDs are associated with an increased incidence of prostate cancer in both Caucasians\nand African Americans. These data suggest that the overall reduced risk is accounted\nfor by the non-Caucasian, non-African Americans populations in the study. These\ndata suggest that TZDs may be beneficial for reducing certain cancers in\ncertain populations. Specific molecular abnormalities in specific cancers and\nthe genetic background of different populations may account for these apparently\ndifferent results.Although this\nstudy was quite strong, we suggest the following for future investigations: (1) separate\nTZD-users into those using rosiglitazone and those using pioglitazone. In the\ncardiovascular risk studies, it was shown that rosiglitazone increases the risk\nwhile pioglitazone decreases the risk [78]. (2) Evaluate the impact of\nthe duration of TZD exposure on risk of cancer development. (3) Determine the\ninfluence of TZDs on the behavior of existing cancers.7. CONCLUSIONSIn this article,\nwe reviewed literature on the roles of PPARγ in cancer with an emphasis on those that\nsuggest a proneoplastic function for the receptor. PPARγ, unlike MYC, RAS, or p53, is neither a strong\ntumor promoter nor a tumor suppressor. However, it may function as a\n“conditional tumor promoter” or a “conditional tumor suppressor” that modulates\nthe tumorigenic process depending upon cellular conditions, tumor types, or\ngenetic background of an animal strain or human individuals. TZDs, as a class\nof pharmacological agent, may have receptor-independent antineoplastic effects,\nespecially at doses higher than diabetic doses or after long-term use and\naccumulation. 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