| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
Carcinogenesis |
Department of Toxicology, Oncology and Molecular Pathology Unit, University of Cagliari, 09124 Cagliari, Italy [G. M. L-C., A. P., R. L., A. C.], and Department of Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania 15261 [H. S.]
 |
ABSTRACT |
|---|
 Top ABSTRACT INTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-glutamyl
transpeptidase or placental glutathione S-transferase
(GSTP)-positive hepatic hyperplastic lesions. In this study, we have
examined the effect of the hormone triiodothyronine (T3), which,
similarly to peroxisome proliferators, is a strong liver mitogen and a
ligand of nuclear receptors, on the growth of GSTP-positive nodules
generated by the resistant hepatocyte model and on the development of
hepatocellular carcinoma. Hepatic hyperplastic nodules were induced in
male Fischer rats by a single dose (150 mg/kg) of diethylnitrosamine,
followed by a 2-week exposure of the animals to 2-acetylaminofluorene
and partial hepatectomy. Nine weeks after diethylnitrosamine
administration, rats were switched to a diet containing 4 mg/kg T3 for
1 week (experiment 1) and sacrificed during T3 feeding or were exposed
to seven cycles of T3-supplemented diet (1 week/month per 7 months),
and sacrificed 6 months after the last cycle (experiment 2). Results
showed that T3 treatment for 1 week caused a 70% reduction in the
number of GSTP-positive nodules (14/cm2 in T3-fed rats
versus 44/cm2 of control animals), as well
as GSTP-positive area (12% versus 43% of controls).
Reduction in the number of GSTP-positive nodules observed 1 week after
T3 feeding was associated with a strong increase in the labeling index
of enzyme-altered nodules compared with that of controls (labeling
index was 64 and 31%, respectively). No significant differences in the
apoptotic index were observed between the two groups. Results from
experiment 2 did reveal that although rats treated with
diethylnitrosamine + 2-acetylaminofluorene developed 100%
hepatocellular carcinoma and 33% of them showed lung metastasis, only
50% of rats exposed to repeated cycles of triiodothyronine developed
hepatocellular carcinoma with no lung metastasis. This study indicates
that cell proliferation per se might not necessarily
represent a promoting condition for putative preneoplastic lesions and
demonstrates an anticarcinogenic effect of T3. |
INTRODUCTION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-glutamyl transpeptidase, or GSTP staining
(12, 13, 14)
. The latter effect has been attributed to the
inhibitory action of these agents on the marker enzyme used to identify
preneoplastic lesion (14)
and not to a real
growth-inhibitory effect. However, Chen et al.
(15)
have shown that a short-term exposure to the PP
ciprofibrate reduced from 40% to <5% the L.I. of preneoplastic
nodules generated by the R-H protocol (16)
, and this
effect was associated with a rapid decrease in area and number of the
nodules. This raises the important issue as to whether induction of
liver cell proliferation is always a promoting condition for
preneoplastic lesions or whether the nature of the proliferative
stimulus is important in determining the type of response of carcinogen
altered cells. The hormone T3 resembles PPs in that: (a) it is a ligand of a nuclear receptor (TRs) of the same superfamily of steroid hormone nuclear receptors (17) ; (b) it is an inducer of peroxisome proliferation (18) ; and (c) it is a potent hepatomitogen (19 , 20) . However, the effect of T3 on the hepatocarcinogenic process is not known. Recently, evidence was obtained in our laboratory that a short exposure to a mitogenic dose of T3 exerts an inhibitory effect on the number of DENA-induced GSTP-positive hepatocytes.4 To further investigate the effect of hepatocyte proliferation induced by primary mitogens on the growth of carcinogen-induced putative preneoplastic lesions, we have examined the effect of T3 on the progression of hepatic nodules, induced in rats by the R-H model, to HCCs.
The results demonstrate that T3 administration for 1 week, despite its powerful mitogenic capacity, resulted in a 70% reduction of the number of GSTP-positive lesions with no increase in the size of the remaining nodules. In addition, repeated exposures of nodule-bearing rats to T3 caused a 50% reduction in the incidence of HCCs and 100% inhibition of lung metastasis. Our data add further support to the notion that the growth response of preneoplastic lesions is dependent upon the nature of the proliferative stimulus and indicate that T3 possesses anticarcinogenic effect in the liver.
|
MATERIALS AND METHODS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
Experimental Protocol I.
Rats were injected i.p. with a single dose of diethylnitrosamine
(DENA), dissolved in saline, at the dose of 150 mg/Kg body weight (Fig. 1)
. After a 2-week recovery period, rats were placed on a diet
containing 0.02% 2-AAF for 1 week and then subjected to a standard
two-thirds PH and continued for an additional week on the
2-AAF-containing diet. Rats were then returned to the basal diet for 5
weeks and then divided into two groups; the first group was maintained
on a basal diet, while the second group was switched to a diet
containing 4 mg/kg of T3 for 1 week and then sacrificed. Depending on
the experiment, BrdUrd (20 mg/ml) was continuously released through
s.c. implanted osmotic minipumps (Model 2 ML1, rate of release 10
µl/h/7 days; Alzet Co., Palo Alto, CA), or it was dissolved in
drinking water (1 mg/ml) and given ad libitum for the last 7
days. In some experiments, rats subjected to the R-H model, as
described above, were sacrificed at 2, 4, and 7 days after starting of
the T3 diet (see Tables 2
3
).
|
|
|
). After the seventh T3 cycle, rats were placed on a basal diet and
sacrificed 16 months after initiation (6 months after the last T3
cycle).
|
Double Labeling of BrdUrd- and GSTP-positive Hepatocytes in
DENA-initiated Rat Liver.
BrdUrd incorporation into nuclei was determined using an anti-BrdUrd
monoclonal antibody (Becton Dickinson Immunocytometry Systems, San
Jose, CA) and Dako Envision peroxidase mouse (K4001; Dako Corp.,
Carpinteria, CA). Briefly, tissue sections were exposed to 0.3%
hydrogen peroxide in ethanol for 10 min to block endogenous peroxidase,
treated with 2 N HCl for 1 h and incubated with
trypsin 0.1% for 20 min and then with normal goat serum for 20 min at
room temperature. The sections were then incubated for 2 h with an
anti-BrdUrd monoclonal antibody (1:200) and for 30 min with peroxidase
goat antimouse IgG. The sites of peroxidase binding were detected with
diaminobenzidine. A segment of duodenum, an organ with a high rate of
cell proliferation, was included from each rat to confirm delivery of
the DNA precursor. The location of GSTP in the liver was determined by
using an antirat GSTP polyclonal antibody (Biotrin, Dublin, Ireland)
and Dako Envision alkaline phosphatase goat antirabbit (K4018; Dako
Corp.). The sites of phosphatase binding were detected with
5-bromo-4-chloro-3-indolyl phosphate/nitro blue tetrazolium substrate
system (K598, Dako Corp.).
Measurement of GSTP-positive Nodules.
GSTP-positive foci were measured with a computer-assisted image
processor, programmed for the three-dimensional calculation by Campbell
et al. (21)
. Only foci >76 µm in diameter
were measured.
Determination of Labeling Index.
Random microscope fields were scored for BrdUrd-positive hepatocytes
within GSTP-positive lesions. The L.I. was calculated as
BrdUrd-positive hepatocyte nuclei/100 hepatocyte nuclei. At least 2500
hepatocytes/rat were scored. The same procedure was used to obtain the
L.I. for surrounding GSTP-negative hepatocytes.
Determination of Apoptotic Index.
The incidence of apoptotic bodies within randomly selected nodules was
determined in H&E-stained sections by scoring at least 3500
hepatocytes/rat. Only apoptotic bodies containing nuclear fragments
were recorded. The A.I. was calculated as number of apoptotic
bodies/100 hepatocytes.
Classification of Liver Tumors.
Histological typing of liver tumors was performed according to the
classification proposed in "Histological Typing of Liver Tumors of
the Rat" (22)
.
Statistical Analysis.
Comparison between treated and control group was performed by
Student’s t test.
|
RESULTS |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
. No evidence of liver cell damage could be observed throughout the
experimental period. The concentration of 4 mg/kg of T3 was selected
for all future experiments.
|
. Feeding T3 for 1 week caused a dramatic change in the macroscopic
appearance of the liver. Indeed, most of T3-fed rats exhibited a liver
characterized by a smooth surface, with only a few protruding nodules.
Accordingly, histological observation of liver sections stained with
H&E did reveal the presence of very few nodules in T3-fed rats, in
contrast with the large number found in DENA + 2-AAF + PH group. Quantification of the number of GSTP-positive nodules
in T3-treated rats showed a 3-fold reduction in their number (from 41
to 14; Table 1
). Reduction of the number of GSTP-positive nodules was
accompanied by a decrease in the percentage of area occupied by
GSTP-positive hepatocytes (Fig. 4
and Table 1
). Interestingly, the reduction in the number of
GSTP-positive nodules by T3 was associated with an increased
proliferative activity of hepatocytes both in the residual
GSTP-positive nodules (L.I., 64% versus 42% of controls)
as well as in surrounding liver (L.I., 31% versus 7% of
controls). Size distribution of the nodules in the two groups (Fig. 5)
showed that no selective growth of some subpopulations of putative
preneoplastic nodules had occurred in T3-treated rats.
|
|
|
, although T3 feeding for 1 week exerted a strong inhibitory effect on
the number of GSTP-positive nodules, confirming the results presented
in Table 1
, treatment with T3 for only 2 or 4 days did not cause any
significant change in number and/or size of GSTP-positive nodules. L.I.
of hepatocytes was determined by analyzing the number of
BrdUrd-positive hepatocyte nuclei within the GSTP-positive nodules,
using a double immunohistochemical technique. As shown in Fig. 6
and Table 3
, feeding of T3 for 2 days caused a striking increase in L.I. of
GSTP-positive nodules compared with that of nodules from rats
maintained on a basal diet (51 and 12%, respectively); the range of
L.I. was 47–57% in nodules from T3-treated rats versus
10–24% of controls. An increased L.I. in T3-liver nodules was also
observed at 4 days (55% versus 21% of controls). As
mentioned above, despite the increased L.I., no difference in the
percentage of GSTP-positive area, either in the mean area of
GSTP-positive nodules between T3-fed rats or the control group, was
observed at 2 and 4 days. Moreover, when distribution analysis of
nodule size was performed, no indication of a shift of T3 nodules to
higher classes was observed (Fig. 7)
.
|
|
, indicate that treatment with T3
for 2 days caused an increase, although statistically not significant,
in the A.I. of the nodules (3.4 versus 2.3 of controls),
thus probably explaining the lack of increase in the size of T3 nodules
(see Table 2
). No statistically significant differences in A.I.
between T3-fed rats and controls could be observed at 4 and 7 days,
clearly indicating that apoptosis was not responsible for the dramatic
reduction in the number of nodules observed after 7 days of T3 feeding.
Interestingly, despite the increased proliferative activity, liver
weight in T3-treated rats was lower than controls (3.7 g/100 g body
weight versus 4.7 g/100 g of controls), most probably as a
consequence of the profound depletion of glycogen caused by the hormone
and leading to an overall decrease in cellular size.
Effect of T3 on the Incidence of HCCs.
To determine whether the inhibitory effect of T3 on GSTP-positive
nodules could result in a decreased incidence of HCC, nodule-bearing
rats were exposed to seven cycles of T3 (1 week/month for 7 months) and
sacrificed 16 months after initiation. Macroscopically, no tumors could
be observed in untreated rats or in animals treated with DENA alone
(data not shown). All rats exposed to the complete R-H
protocol (DENA + AAF + PH) showed multiple tumors,
with some livers weighing up to 60–70 g. Conversely, only 50% of the
rats exposed to T3 following the R-H model showed evidence of tumors.
In contrast to the T3-untreated group, a single clearly defined tumoral
mass was observed in these animals. No livers weighing >50 g were
observed in tumor-bearing animals treated with T3. Histological
observation confirmed the presence of tumors in all rats exposed to
DENA + AAF + PH in the absence of T3 (Table 4)
and revealed that all tumors in this group were classical trabecular
HCCs (Fig. 8A)
, although three of the five tumors seen in the DENA + AAF + PH + T3 group were adenocarcinomas with
frequent cystic or papillary cystic patterns (Fig. 8, C and D)
. Moreover, in the DENA + AAF + PH
group, metastases to the lung were found in 5 of 15 animals (33%; see
Table 4
and Fig. 8B
); no metastases were found in T3-exposed
animals.
|
|
|
DISCUSSION |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
-glutamyl transpeptidase or GSTP (12, 13, 14, 15)
. To know more about the relationship between mitogenesis and preneoplastic growth, in the present study, we have examined the effect of a single or repeated short-term treatment with the hormone T3 on the growth and progression of GSTP-positive nodules generated by the R-H protocol. Two findings were the most significant in this study: (a) a short-term treatment (1 week) with T3 was able to dramatically reduce the number of GSTP-positive nodules; and (b) repeated cycles of T3 to nodule-bearing rats caused a 50% decrease in HCC development and a complete inhibition of lung metastasis.
Loss of GSTP-positive nodules occurred despite a striking increase in hepatocyte proliferation, both within the nodules as well as surrounding liver. Therefore, the mechanism responsible for the disappearance of the nodules by T3 appears to be different from that proposed for ciprofibrate by Chen et al. (15) , who observed an inhibitory effect by this agent on nodule growth.
Another factor influencing growth of preneoplastic lesions is the rate of cell death. Indeed, promoting agents, such as phenobarbital (25) and dioxin (41) , are thought to act, at least in part, by inhibiting apoptosis; on the other hand, dietary restriction and S-adenosyl-methionine, potent inhibitors of carcinogenesis, appear to exert their anticarcinogenic effect by inducing an increased apoptotic incidence in preneoplastic lesions (42, 43, 44) . Our results, however, did not support a significant role for apoptosis in the regression of GSTP-positive nodules induced by T3. Indeed, although it is conceivable that the higher A.I. observed 2 days after T3 might in part explain the lack of increase in nodule size at that particular time point (compared with controls), no difference in A.I. between T3-fed and control rats was observed at later time points.
Although, at the present, it is difficult to draw any conclusion, at least two possibilities can be envisaged to explain the dramatic reduction in the number of nodules observed in T3-fed rats, despite the concomitant increase in hepatocyte proliferation: (a) the loss of GSTP-positive foci is attributable to inhibition of GSTP expression by T3, similarly to what was proposed for PPs (14) , and not a to a real reduction in nodule number; (b) T3, in addition to its mitogenic capacity, might also interfere with the differentiation program by inducing retrodifferentiation of the nodular hepatocytes to normal-appearing cells via loss of their "resistant" phenotype, a rearrangement to single-cell plates, and an integration into the organizational pattern of the surrounding liver (23) . The former possibility (direct inhibition by T3 on GSTP gene expression) appears very unlikely, in virtue of the following: (a) reduction in nodules number was confirmed by analysis of sections stained with H&E; (b) macroscopic observation revealed that livers from T3-fed rats were characterized by a smooth surface, with only a few protruding nodules; and (c) short-term T3 administration did not exert any inhibitory effect on GSTP mRNA or protein levels induced in rat liver by the known GSTP-inducer lead nitrate.4
Thus, remodeling (or regression) induced through a redifferentiation program appears to be the most likely explanation for the loss of hepatic nodules caused by T3. T3 is known to possess a nuclear receptor (TRs) of the same superfamily of receptors of PPs (peroxisome proliferator activated receptors), and retinoic acids (retinoic acid receptors and retinoid X receptors), and these receptors have been shown to exert a profound effect on cellular differentiation (45, 46, 47) . The observation that the histological appearance of HCCs seen in rats treated with T3 was different from that of rats without T3 also suggests that this hormone, via interaction with and activation of its receptor, may have effects on differentiation of putative preneoplastic hepatocytes.
A second and even more important result achieved by this study was the reduction of HCC development and inhibition of metastases to the lung in rats exposed to repeated cycles of T3. To our knowledge, it has been extremely difficult thus far to reduce the progression of hepatic nodules generated by genotoxic agents to HCC. The fact that the anticarcinogenic effect played by T3 is associated with several cycles of hepatocyte proliferation further supports the notion that cell proliferation per se may not necessarily represent a carcinogenic and/or promoting condition. On the other hand, our data suggest that certain proliferative stimuli may play an anticarcinogenic effect, probably by causing a redifferentiation of preneoplastic cells.
|
FOOTNOTES |
|---|
1 Supported in part by funds from Associazione
Italiana Ricerca sul Cancro (Milano, Italy) and Ministero
dell’Università e della Ricerca Scientifica e Tecnologica (MURST
Cofin ex-40% and 60%), Rome, Italy. 
2 To whom requests for reprints should be
addressed, at Dipartimento di Tossicologia, Sezione di Oncologia e
Patologia Molecolare,Via Porcell 4, 09124 Cagliari, Italy. Phone:
011-39-070-6758345; Fax: 011-39-070-666062.
3 The abbreviations used are: PP, peroxisome
proliferator; T3, 3,5,3'-triiodo-L-thyronine; GSTP,
glutathione S-transferase; DENA, diethylnitrosamine;
2-AAF, 2-acetylaminofluorene; R-H, resistant hepatocyte;
BrdUrd, bromodeoxyuridine; L.I., labeling index; A.I., apoptotic
index; PH, partial hepatectomy; HCC, hepatocellular carcinoma.
Received 8/17/99. Accepted 12/ 2/99.
|
REFERENCES |
|---|
|
TopABSTRACTINTRODUCTIONMATERIALS AND METHODSRESULTSDISCUSSIONREFERENCES |
|---|
This article has been cited by other articles:
|
|
 |
|
  K. Kubota, J. Soeda, R. Misawa, M. Mihara, S. Miwa, H. Ise, M. Takahashi, and S. Miyagawa Bone marrow-derived cells fuse with hepatic oval cells but are not involved in hepatic tumorigenesis in the choline-deficient ethionine-supplemented diet rat model Carcinogenesis, February 1, 2008; 29(2): 448 - 454. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Perra, M. Pibiri, P. Sulas, G. Simbula, G. M. Ledda-Columbano, and A. Columbano {alpha}-lipoic acid promotes the growth of rat hepatic pre-neoplastic lesions in the choline-deficient model Carcinogenesis, January 1, 2008; 29(1): 161 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Michienzi, B. Bucci, C. Verga Falzacappa, V. Patriarca, A. Stigliano, L. Panacchia, E. Brunetti, V. Toscano, and S. Misiti 3,3',5-Triiodo-L-thyronine inhibits ductal pancreatic adenocarcinoma proliferation improving the cytotoxic effect of chemotherapy J. Endocrinol., May 1, 2007; 193(2): 209 - 223. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Fava, Y. Ueno, S. Glaser, H. Francis, S. DeMorrow, L. Marucci, M. Marzioni, A. Benedetti, J. Venter, B. Vaculin, et al. Thyroid hormone inhibits biliary growth in bile duct-ligated rats by PLC/IP3/Ca2+-dependent downregulation of SRC/ERK1/2 Am J Physiol Cell Physiol, April 1, 2007; 292(4): C1467 - C1475. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Columbano, M. Pibiri, M. Deidda, C. Cossu, T. S. Scanlan, G. Chiellini, S. Muntoni, and G. M. Ledda-Columbano The Thyroid Hormone Receptor-{beta} Agonist GC-1 Induces Cell Proliferation in Rat Liver and Pancreas Endocrinology, July 1, 2006; 147(7): 3211 - 3218. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C.-C. Yen, Y.-H. Huang, C.-Y. Liao, C.-J. Liao, W.-L. Cheng, W.-J. Chen, and K.-H. Lin Mediation of the inhibitory effect of thyroid hormone on proliferation of hepatoma cells by transforming growth factor-beta J. Mol. Endocrinol., February 1, 2006; 36(1): 9 - 21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
E. M. de Almeida Vasconcelos Fonseca, C. E. A. Chagas, R. P. Mazzantini, R. Heidor, T. P. Ong, and F. S. Moreno All-trans and 9-cis retinoic acids, retinol and {beta}-carotene chemopreventive activities during the initial phases of hepatocarcinogenesis involve distinct actions on glutathione S-transferase positive preneoplastic lesions remodeling and DNA damage Carcinogenesis, November 1, 2005; 26(11): 1940 - 1946. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G M Ledda-Columbano, A Perra, M Pibiri, F Molotzu, and A Columbano Induction of pancreatic acinar cell proliferation by thyroid hormone J. Endocrinol., June 1, 2005; 185(3): 393 - 399. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Hayashi, T. Tamura, J. Kuroda, H. Ohnota, N. Shibata, M. Akahane, Y. Kashida, and K. Mitsumori Different Inhibitory Effects in the Early and Late Phase of Treatment with KAT-681, a Liver-Selective Thyromimetic, on Rat Hepatocarcinogenesis Induced by 2-Acetylaminofluorene and Partial Hepatectomy after Diethylnitrosamine Initiation Toxicol. Sci., March 1, 2005; 84(1): 22 - 28. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G.M. Ledda-Columbano, M. Pibiri, F. Molotzu, C. Cossu, L. Sanna, G. Simbula, A. Perra, and A. Columbano Induction of hepatocyte proliferation by retinoic acid Carcinogenesis, November 1, 2004; 25(11): 2061 - 2066. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. M. Ledda-Columbano, A. Perra, D. Concas, C. Cossu, F. Molotzu, C. Sartori, H. Shinozuka, and A. Columbano Different Effects of the Liver Mitogens Triiodo-Thyronine and Ciprofibrate on the Development of Rat Hepatocellular Carcinoma Toxicol Pathol, January 1, 2003; 31(1): 113 - 120. [Abstract] [PDF]
|
|
|
|
|
|
P. Bannasch, T. Haertel, and Qin Su Significance of Hepatic Preneoplasia in Risk Identification and Early Detection of Neoplasia Toxicol Pathol, January 1, 2003; 31(1): 134 - 139. [Abstract] [PDF]
|
|
|
|
|
|
M. Evert, T. Ott, A. Temme, K. Willecke, and F. Dombrowski Morphology and morphometric investigation of hepatocellular preneoplastic lesions and neoplasms in connexin32-deficient mice Carcinogenesis, May 1, 2002; 23(5): 697 - 703. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
G. A. Wood, J. E. Korkola, and M. C. Archer Tissue-specific resistance to cancer development in the rat: phenotypes of tumor-modifier genes Carcinogenesis, January 1, 2002; 23(1): 1 - 9. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 L. Xu, L. Hui, S. Wang, J. Gong, Y. Jin, Y. Wang, Y. Ji, X. Wu, Z. Han, and G. Hu Expression Profiling Suggested a Regulatory Role of Liver-enriched Transcription Factors in Human Hepatocellular Carcinoma Cancer Res., April 1, 2001; 61(7): 3176 - 3181. [Abstract] [Full Text]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Cancer Research | Clinical Cancer Research |
| Cancer Epidemiology Biomarkers & Prevention | Molecular Cancer Therapeutics |
| Molecular Cancer Research | Cancer Prevention Research |
| Cancer Prevention Journals Portal | Cancer Reviews Online |
| Annual Meeting Education Book | Meeting Abstracts Online |
