february 2012 CANCER DISCOVERY | 117

views

Cancers of the Colon and Rectum: identical or Fraternal Twins?Theodore S. Hong1, Jeffrey W. Clark2, and Kevin M. Haigis3

summary: Colorectal cancer represents a major cause of cancer morbidity and mortality, with approximately 1.2 million cases and 600,000 deaths worldwide each year. Because of the anatomic continuity of the colon into the rectum, cancers affecting these organs have historically been considered equivalent. In this Prospective, we discuss the clinical and experimental data suggesting that colon cancer and rectal cancer are highly related, but distinct, diseases. Reconsidering the relationship between these cancers has implications for the development of new therapeutic paradigms. Cancer Discovery; 2(2); 117–21. ©2012 AACR.

ProsPective

introductionColorectal cancer represents a major cause of cancer mor-

bidity and mortality, with approximately 1.2 million cases and 600,000 deaths worldwide each year (1). The colon and rectum are related anatomically, and therefore colon cancers and rectal cancers are typically considered to be essentially the same disease. Yet, they differ clinically in one very impor-tant aspect: rectal cancer has a substantially greater rate of local recurrence (2–4). Because of this increased risk, patients with locally advanced rectal cancer receive a combination of radiation and chemotherapy before surgery, with postopera-tive chemotherapy to follow. In contrast, patients with colon cancer proceed directly to surgery and are given chemother-apy only if lymph nodes are involved or if they have other high-risk pathologic features.

This difference in the treatment paradigm has led to some confusion regarding the development of future strategies for colon cancer and rectal cancer. Are the distinct clinical re-sponses of colon cancers and rectal cancers attributable to inherent biological differences or simply to medical treat-ment issues? The prevailing philosophy is that rectal cancer is colon cancer with a local control problem. As a result, the therapeutic paradigm is focused primarily on improving the local control rate through surgical and radiation-based strat-egies. Moreover, the paradigm to control metastatic relapse continues to be directly extrapolated from colon cancer stud-ies, which specifically exclude rectal cancer because of the confounding impact of chemoradiation. Here, we discuss the clinical similarities and differences between colon cancer and rectal cancer and the scientific data suggesting similarities and differences.

AnAtomic influences on locAl recurrence

The surgical accessibility of cancers of the colon and rec-tum plays a major role in their distinct clinical management. Although the colon and rectum represent 2 separate regions of a contiguous organ—the large intestine—the anatomic distinction between the colon and rectum relates to their intraperitoneal versus retroperitoneal locations within this organ. The colon begins in the right lower quadrant of the peritoneal cavity at the ileocecal valve, travels superiorly to the hepatic flexure in the right upper quadrant, comes across anteriorly from right to left to the splenic flexure, and pro-ceeds inferiorly to the left lower quadrant. At the left lower quadrant, the colon swings medially and exits the peritoneal cavity into the pelvis.

In contrast to the abdomen, where there is ample room for a surgeon to obtain widely negative margins, the pelvic inlet is quite narrow. The rectum itself is in the posterior pelvis and surrounded by perirectal fat, which is enveloped by an avascular fascial plane known as the mesorectal fascia. This mesorectal envelope houses the regional lymph nodes of the rectum. The mesorectum is tightly bounded by the sacrum and associated sacral nerves posteriorly, the iliac vessels and branches of the sacral nerves laterally, and the genitourinary structures anteriorly. In men, the upper rectum borders the bladder anteriorly, and the middle and lower rectum lies ad-jacent to the seminal vesicles and the prostate. In women, the upper rectum is bounded by the uterus and the middle and lower rectum are bounded by the posterior vagina. As the rec-tum descends inferiorly/distally towards the anal canal, the pelvis tapers narrowly. Because the pelvic space harboring the rectum is significantly narrower than the abdomen, and the lower pelvis is narrower than the upper pelvis, the possibility of a clean resection becomes more challenging as the surgeon attempts a rectal, compared with a colonic, resection. As a result, there is a greater likelihood of local recurrence.

mAnAgement of locAlly AdvAnced rectAl cAncer versus colon cAncer

When a patient is suspected of having locally advanced co-lon cancer (T3–T4a or node-positive, excluding T4b), surgery

Authors’ Affiliations: 1Department of Radiation Oncology, 2Department of Medicine, and 3Molecular Pathology Unit, Massachusetts General Hospital, Boston, Massachusetts Corresponding author: Kevin M. Haigis, Molecular Pathology Unit, 149 13th Street, 7.372, Charlestown, MA 02129. Phone: 617-643-0070; Fax: 617-726-5684; E-mail: khaigis@partners.org doi: 10.1158/2159-8290.CD-11-0315 ©2012 American Association for Cancer Research.

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from

118 | CANCER DISCOVERY february 2012  www.aacrjournals.org

views

as well as the fact that the neoadjuvant approach for rectal cancer makes it difficult to be certain of the true pathologic stage for all patients.

clinicAl differences between colon cAncer And rectAl cAncer: beyond locAl fAilure

In addition to the greater incidence of local recurrence, differences in clinical patterns of failure have been noted be-tween colon cancer and rectal cancer. Colon cancer relapse is most commonly manifested by primary recurrence in the liver or lung, with liver metastases up to 4 times as likely as lung metastases. In contrast, rectal cancer carries a greater risk of lung metastases, which in some studies has equaled or exceeded the risk of liver metastases (8).

is the first treatment if the metastatic survey is negative (Fig. 1, Table 1). In this setting, surgery is associated with excellent local control, with local failure rates between 3% and 5% (2). If the lymph nodes are involved (stage III dis-ease), a patient will have approximately 60% risk of distant, metastatic relapse, which can be decreased by approximately 20% (relative risk reduction of one third) with the addi-tion of a fluoropyrimidine-based adjuvant systemic chemo-therapy (5). In some cases of high-risk features, such as T4 cancers, clinical evidence of perforation at surgery, poorly differentiated histology, lymphovascular invasion, or insuf-ficient node sampling (,12 nodes), some clinicians will of-fer adjuvant therapy because these high-risk features may be associated with a risk of recurrence similar to that of stage III disease.

Locally advanced rectal cancer is associated with a sub-stantially greater risk of a local recurrence. In the Swedish Rectal Study, one of the first randomized trials evaluating the use of preoperative radiation therapy in rectal cancer, patients with stage II disease who had surgery alone had a local relapse risk of 22%, and patients with stage III disease had a local relapse risk of 46% (3). The suspected reasons for this high rate of relapse were the anatomic restraint on sur-gical resection (discussed previously in this article) and the technical nature of the operation. Historically, the surgeon would bluntly mobilize the rectum itself by hand, leading to a high frequency of positive margins and retained nodal tis-sue. The likelihood of local recurrence and subsequent death caused by rectal cancer is markedly greater in the setting of a positive margin (4).

For this reason, modern surgical techniques require the surgeon to perform a total mesorectal excision, whereby the surgeon sharply excises the mesorectal fascia to decrease the risk of leaving disease behind. Nevertheless, despite this improved surgical technique, radiation still confers a local control benefit (6). Because of the accepted increased risk of local recurrence of locally advanced rectal cancer, the current standard course of therapy is preoperative chemo-radiation, followed by surgery (Fig. 1). As a result of the significant downstaging that occurs with chemoradiation, however, the original nodal status is never known, and pa-tients are recommended to complete a course of adjuvant chemotherapy.

The most typical adjuvant chemotherapy after surgery for either colon cancer or rectal cancer is FOLFOX, a 3-drug regi-men of 5-fluorouracil, leucovorin, and oxaliplatin. The ratio-nale for this regimen derives largely from the Multicenter International Study of Oxaliplatin/5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial (7), in which investigators showed an improved disease-free survival and overall survival in patients with stage III colon cancer. Even though a similar trial has not been completed for rectal cancer, it is widely assumed that the overall sur-vival between colon and rectal cancer is similar stage-for-stage, given current therapeutic approaches. Retrospective studies that have evaluated this question have been mixed in terms of whether there might be any differences in re-sponse between the diseases. These analyses are compli-cated, however, by changes in the standard approach to adjuvant therapy for both colon and rectal cancer over time,

Stage Ta Nb Mc

0 Tis N0 M0

I T1 N0 M0

T2 N0 M0

IIA T3 N0 M0

IIB T4a N0 M0

IIC T4b N0 M0

IIIA T1–T2 N1/N1c M0

T1 N2a M0

IIIB T3–T4a N1/N1c M0

T2–T3 N2a M0

T1–T2 N2b M0

IIIC T4a N2a M0

T3–T4a N2b M0

T4b N1–N2 M0

IVA Any T Any N M1a

IVB Any T Any N M1

aPrimary tumor (T) : TX, primary tumor cannot be assessed; T0, no evidence of primary tumor; Tis, carcinoma in situ: intraepithelial or invasion of lamina propria; T1, tumor invades submucosa; T2, tumor invades muscularis propria ; T3, tumor invades through the muscularis propria into pericolorectal tissues; T4a, tumor penetrates to the surface of the visceral peritoneum; T4b, tumor directly invades or is adherent to other organs or structuresbregional lymph nodes (N) : NX, regional lymph nodes cannot be assessed; N0, no regional lymph node metastasis; N1, metastasis in 1–3 regional lymph nodes; N1a, metastasis in one regional lymph node; N1b, metastasis in 2–3 regional lymph nodes; N1c, tumor deposit(s) in the subserosa, mesentery, or nonperitonealized pericolic or perirectal tissues without regional nodal metastasis; N2, metastasis in 4 or more regional lymph nodes; N2a, metastasis in 4–6 regional lymph nodes; N2b, metastasis in 7 or more regional lymph nodescDistant metastasis (M) : M0, no distant metastasis; M1, distant metastasis; M1a, metastasis confined to one organ or site (e.g., liver, lung, ovary, nonregional node); M1b, metastases in more than one organ/site or the peritoneum.

table 1. Colorectal cancer staging

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from

february 2012 CANCER DISCOVERY | 119

views

Similar to local recurrence, the discrepancy in meta-static recurrence is thought to be determined on the basis of anatomy, rather than on biology. Embryologically, the rectum and left side of the colon (from the distal one-third of the transverse colon) arise from the hindgut, whereas the colon proximal to that arises from the midgut. This is accompanied by a difference in blood supply, which may account for the difference in the pattern of metastases. There is a closed portal venous loop by which the intra-peritoneal colon drains directly to the portal vein and thus the first major organ that any circulating tumor cells en-counter is the liver. The inferior rectal vein, which drains the distal rectum, flows directly to the inferior vena cava, which in turn circulates through the heart and into the pulmonary artery by way of the right atrium and ventricle. Thus, again, the first major organ encountered, in this case the lung, is the greatest-risk site of metastasis. Although anatomy provides a convenient explanation for differ-ences in metastatic potential, robust data are lacking as to whether this simple hypothesis is completely accurate or whether there might be differences in the biology of can-cers arising in the colon versus rectum that might account for some of the difference in the pattern of metastases. In other systems, for example breast cancer, differences in metastatic potential cannot be explained anatomically but instead have been linked to the activity of specific genes in distinct subsets of breast cancers (9).

The distinct metastatic behavior of colonic and rectal cancers is clear; however, little is known about whether there might be any difference in survival of patients with metastatic colon or rectal cancer because most of the recent trials that have evaluated this question include

patients with either cancer and have not been analyzed for a possible difference between the two. Given the over-all evidence suggesting that any difference that might exist once differences in stage at presentation are elimi-nated may primarily result from differences in genetics between subsets of patients with colon cancer (right-sided vs. left-sided) and rectal cancer, most of the current emphasis has been on evaluating the potential genetic differences (10, 11).

ePigenetic And genetic distinctions between colon And rectAl cAncers

The advent of genomic technologies has allowed for the molecular characterization of cancers in unprecedented detail. For rectal cancer in particular, gene expression pro-filing has been used to identify a gene signature of local recurrence after chemoradiation therapy, but, for reasons described previously, there is no colon cancer comparison in this study (12). In addition, gene expression profil-ing has led to the identification of biomarkers related to colorectal cancer staging, metastatic behavior, and clini-cal response, but these studies typically have not evalu-ated colon cancer and rectal cancer separately (13–15). For studies in which data are available for anatomic location, there are significant differences in mRNA and miRNA expression between colon cancers and rectal cancers (15, 16). It remains unclear, however, whether these gene ex-pression differences result from the distinct developmen-tal origins of the colon and rectum and whether they affect clinical parameters such as metastatic behavior or therapeutic response.

Descending

colon

Sigmoid

colon

Rectum

Node-positive or

T3–T4 with high-risk features

Surgery (subtotal colectomy)

Fluoropyrimidine-based chemotherapy

(5-fluorouracil/leucovorin,

capecitabine, or FOLFOX)

Fluoropyrimidine-based chemotherapy

(5-fluorouracil/leucovorin, capecitabine, or FOLFOX)

Node-positive or T3–T4

45–50.4 Gy 3 Gy/fx ($5 weeks) with

fluoropyrimidine-based chemotherapy

Surgery (total mesorectal excision)

figure 1. Distinct treatment courses for cancers of the colon and rectum. Because of the enhanced risk of local recurrence, patients with rectal cancer receive neoadjuvant chemoradiation before surgical resection, whereas patients with colon cancer receive chemotherapy after surgery.

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from

120 | CANCER DISCOVERY february 2012  www.aacrjournals.org

views

Genome sequencing provides perhaps the most compel-ling evidence that colon and rectal cancers are related but distinct. A survey of publicly available sequencing data that are annotated for anatomic location (http://www.sanger.ac.uk/genetics/CGP/cosmic/) identifies several genes that are mutated at similar frequencies in both types of cancers, including FBXW7, KRAS, NF1, NRAS, PIK3CA, PTEN, and SMAD4 (Table 2). However, several genes are also identified that discriminate between colon and rectal cancers. Colon cancers have relatively frequent mutations in BRAF, CTNNB1, PIK3R1, and SRC, whereas rectal can-cers are more commonly mutant for APC, ERBB2, STK11, and TP53 (Table 2). Some of these data are consistent with known differences between colon and rectal cancers. For example, BRAF mutations occur most commonly in ser-rated polyps, a specific subtype of colorectal cancer precur-sor that arises predominantly in the right-side colon (17). Although the link between rectal cancer and the STK11 mutation has not been studied in detail, single-nucleotide polymorphisms in STK11 have been associated with in-creased risk of developing the disease (18). By contrast, although SRC mutations have been reported in colorectal cancer, the distinct separation between colon cancer and rectal cancer has not been explored (19). These genetic data suggest that cancers in the colon and rectum select for mutations in an overlapping, but distinct, set of signal-ing pathways. As with differences in gene expression pro-files, the clinical significance of these distinct mutational profiles is unclear.

imPlicAtions for therAPy

The distinctions between colon cancer and rectal cancer have important implications for therapeutic development. To begin, the current therapeutic paradigm for rectal cancer—neoadjuvant chemoradiation—provides a different framework for the identification of new therapies. Several randomized trials have shown that patients who had a pathologic com-plete response to chemoradiation have a significantly better outcome, particularly in regard to distant metastases (20, 21). The link between pathologic complete response and disease outcomes has prompted a generation of phase I/II studies for rectal cancer that have evaluated the impact of new agents in an attempt to improve the pathologic complete response rate.

Nevertheless, these trials typically are not designed to evaluate the same agent in the setting of postoperative che-motherapy. Rather, patients are treated postoperatively with FOLFOX based on the MOSAIC trial, which specifically excluded patients with rectal cancer (7). This type of trial design represents a potential conflict in therapeutic devel-opment. On the one hand, new agents are added to radia-tion in hopes of improving disease outcomes. On the other hand, the component of therapy most likely to impact overall survival is the postoperative chemotherapy. On the basis of the results of the trials referenced previously, if a new agent convincingly improves pathologic complete response rates, one should consider studying it in combination with post-operative chemotherapy, unless there is scientific evidence that the drug’s mechanism of action is strictly the result of radiosensitization.

Moving forward, this discrepancy will need to be resolved before further resources are invested in the integration of new agents into chemoradiation. Patterns of failure clearly indicate that the metastatic risk in rectal cancer greatly outweighs the local recurrence with current standard ther-apy (20). Thus, a pathway of development to improve the pathologic complete response rate without an attempt to mitigate the metastatic risk via the same agent will likely be unsuccessful.

The finding of genetic differences between colon and rec-tal cancers also has potential practical implications for eval-uating investigational agents. Elucidation of the genomic landscape of specific cancers has ushered in the era of gen-otype-driven targeted therapy. As such, the anatomic and physiologic distinction between cancers of the colon and rectum may become less significant when, in the long term, cancers are classified primarily on the basis of mutational profiles. Nevertheless, the distinction between the muta-tional spectra of colon cancer and rectal cancer is still im-portant. Because broad tumor genotyping is not currently commonplace in the clinic, it can be extremely difficult to identify the patients who will benefit from a particular targeted therapy, especially when a particular mutation is rare. This concept is readily apparent in the case of EGFR-mutant non–small cell lung cancer. Although activating mutations in EGFR occur at a frequency of 10% in patients with non–small cell lung cancer, they are strongly enriched in female Asian nonsmokers with adenocarcinomas (22). By extension, clinicians are aware that these patients are more likely to benefit from EGFR inhibitors. Similarly,

Anatomic site

Genes Colon Rectum

APC 28% (208/738) 51% (48/94)

BRAF 14% (1079/7618) 4% (102/2810)

CTNNB1 7% (38/528) 0% (1/236)

ERBB2 0% (0/30) 6% (3/52)

FBXW7 17% (20/121) 21% (8/39)

KRAS 35% (1736/4958) 36% (489/1343)

NF1 10% (8/78) 7% (1/14)

NRAS 2% (5/223) 1% (1/69)

PIK3CA 12% (63/509) 10% (44/441)

PIK3R1 3% (6/174) 0% (0/14)

PTEN 9% (18/203) 12% (9/77)

SMAD4 10% (15/151) 10% (5/52)

SRC 5% (9/191) 0% (0/101)

STK11 12% (5/41) 33% (4/12)

TP53 49% (1530/3138) 66% (402/610)

table 2. Genes for which mutational data are available for colonic and rectal cancers

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from

february 2012 CANCER DISCOVERY | 121

views

9. Kang Y. New tricks against an old foe: molecular dissection of metas-tasis tissue tropism in breast cancer. Breast Dis 2006;26:129–38.

10. Kalady MF, Sanchez JA, Manilich E, Hammel J, Casey G, Church JM. Divergent oncogenic changes influence survival differences between colon and rectal adenocarcinomas. Dis Colon Rectum 2009;52:1039–45.

11. Benedix F, Kube R, Meyer F, Schmidt U, Gastinger I, Lippert H. Comparison of 17,641 patients with right- and left-sided colon can-cer: differences in epidemiology, perioperative course, histology, and survival. Dis Colon Rectum 2010;53:57–64.

12. Liersch T, Grade M, Gaedcke J, Varma S, Difilippantonio MJ, Langer C, et al. Preoperative chemoradiotherapy in locally advanced rectal cancer: correlation of a gene expression-based response signature with recurrence. Cancer Genet Cytogenet 2009;190:57–65.

13. Eschrich S, Yang I, Bloom G, Kwong KY, Boulware D, Cantor A, et al. Molecular staging for survival prediction of colorectal cancer patients. J Clin Oncol 2005;23:3526–35.

14. Bruin SC, Klijn C, Liefers GJ, Braaf LM, Joosse SA, van Beers EH, et al. Specific genomic aberrations in primary colorectal cancer are associated with liver metastases. BMC Cancer 2010;10:662.

15. Jorissen RN, Gibbs P, Christie M, Prakash S, Lipton L, Desai J, et al. Metastasis- Associated Gene Expression Changes Predict Poor Outcomes in Patients with Dukes Stage B and C Colorectal Cancer. Clin Cancer Res 2009;15:7642–51.

16. Slattery ML, Wolff E, Hoffman MD, Pellatt DF, Milash B, Wolff RK. MicroRNAs and colon and rectal cancer: differential expres-sion by tumor location and subtype. Gene Chromosome Cancer 2011;50:196–206.

17. Huang CS, Farraye FA, Yang S, O’Brien MJ. The clinical significance of serrated polyps. Am J Gastroenterol 2011;106:229–40; quiz 41.

18. Slattery ML, Herrick JS, Lundgreen A, Fitzpatrick FA, Curtin K, Wolff RK. Genetic variation in a metabolic signaling pathway and co-lon and rectal cancer risk: mTOR, PTEN, STK11, RPKAA1, PRKAG2, TSC1, TSC2, PI3K and Akt1. Carcinogenesis 2010;31:1604–11.

19. Irby RB, Mao W, Coppola D, Kang J, Loubeau JM, Trudeau W, et al. Activating SRC mutation in a subset of advanced human colon can-cers. Nat Genet 1999;21:187–90.

20. Rodel C, Martus P, Papadoupolos T, Fuzesi L, Klimpfinger M, Fietkau R, et al. Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 2005;23:8688–96.

21. Roh MS, Colangelo LH, O’Connell MJ, Yothers G, Deutsch M, Allegra CJ, et al. Preoperative multimodality therapy improves dis-ease-free survival in patients with carcinoma of the rectum: NSABP R-03. J Clin Oncol 2009;27:5124–30.

22. Linardou H, Dahabreh IJ, Bafaloukos D, Kosmidis P, Murray S. Somatic EGFR mutations and efficacy of tyrosine kinase inhibitors in NSCLC. Nat Rev Clin Oncol 2009;6:352–66.

activating SRC mutations are rare in the general colorec-tal cancer population. However, these mutations appear to be entirely absent in rectal cancers, so perhaps they are enriched in a specific subpopulation of patients with colon cancer. Identification of the “at-risk” populations for all of the mutations involved in colon cancer and rectal cancer is the first step toward the establishment of genotype-based therapeutic paradigms.

Disclosure of Potential Conflicts of interestNo potential conflicts of interest were disclosed.

Received December 15, 2011; accepted December 19, 2011; published online February 13, 2012.

ReFeRenCes 1. Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global

cancer statistics. CA Cancer J Clin 2011;61:69–90. 2. Manfredi S, Bouvier AM, Lepage C, Hatem C, Dancourt V, Faivre J.

Incidence and patterns of recurrence after resection for cure of co-lonic cancer in a well defined population. Br J Surg 2006;93:1115–22.

3. Folkesson J, Birgisson H, Pahlman L, Cedermark B, Glimelius B, Gunnarsson U. Swedish Rectal Cancer Trial: long lasting benefits from radiotherapy on survival and local recurrence rate. J Clin Oncol 2005;23:5644–50.

4. Adam IJ, Mohamdee MO, Martin IG, Scott N, Finan PJ, Johnston D, et al. Role of circumferential margin involvement in the local recur-rence of rectal cancer. Lancet 1994;344:707–11.

5. Efficacy of adjuvant fluorouracil and folinic acid in colon cancer. International Multicentre Pooled Analysis of Colon Cancer Trials (IMPACT) investigators. Lancet 1995;345:939–44.

6. Sebag-Montefiore D, Stephens RJ, Steele R, Monson J, Grieve R, Khanna S, et al. Preoperative radiotherapy versus selective post-operative chemoradiotherapy in patients with rectal cancer (MRC CR07 and NCIC-CTG C016): a multicentre, randomised trial. Lancet 2009;373:811–20.

7. Andre T, Boni C, Navarro M, Tabernero J, Hickish T, Topham C, et al. Improved overall survival with oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment in stage II or III colon cancer in the MOSAIC trial. J Clin Oncol 2009;27:3109–16.

8. O’Connell MJ, Martenson JA, Wieand HS, Krook JE, Macdonald JS, Haller DG, et al. Improving adjuvant therapy for rectal cancer by combining protracted-infusion fluorouracil with radiation therapy after curative surgery. N Engl J Med 1994;331:502–7.

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from

2012;2:117-121. Cancer Discovery   Theodore S. Hong, Jeffrey W. Clark and Kevin M. Haigis  Twins?Cancers of the Colon and Rectum: Identical or Fraternal

  Updated version

  http://cancerdiscovery.aacrjournals.org/content/2/2/117

Access the most recent version of this article at:

   

   

  Cited articles

  http://cancerdiscovery.aacrjournals.org/content/2/2/117.full#ref-list-1

This article cites 22 articles, 6 of which you can access for free at:

  Citing articles

  http://cancerdiscovery.aacrjournals.org/content/2/2/117.full#related-urls

This article has been cited by 4 HighWire-hosted articles. Access the articles at:

   

  E-mail alerts related to this article or journal.Sign up to receive free email-alerts

  Subscriptions

Reprints and

  .pubs@aacr.orgDepartment at

To order reprints of this article or to subscribe to the journal, contact the AACR Publications

  Permissions

  Rightslink site. (CCC)Click on "Request Permissions" which will take you to the Copyright Clearance Center's

.http://cancerdiscovery.aacrjournals.org/content/2/2/117To request permission to re-use all or part of this article, use this link

Cancer Research. on October 14, 2020. © 2012 American Association forcancerdiscovery.aacrjournals.org Downloaded from