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Commentary

Correcting the misnomers of epithelialemesenchymalrelations

Jason K. Sicklick, MD*

Division of Surgical Oncology, Department of Surgery, Moores UCSD Cancer Center, University of California, San Diego, CA

a r t i c l e i n f o

Article history:

Received 11 January 2012

Received in revised form

11 February 2012

Accepted 29 February 2012

Available online 18 March 2012

DOI of original article: 10.1016/j.jss.2011.0* Corresponding author. Division of Surgical O

University of California, San Diego, UC San D92093-0987. Tel.: 858 822 3967; fax: 858 228 5

E-mail address: jsicklick@ucsd.edu.0022-4804/$ e see front matter ª 2013 Elsevdoi:10.1016/j.jss.2012.02.063

Shakespeare wrote, “What’s in a name? That which we call

a rose by any other name would smell as sweet.” But what if

we called a rose by another name and it was not so sweet? The

organic gardener andwriter, Colleen Vanderlinden noted that,

“Roses, lilacs, lavender, hyacinthdall of these flowers have

a scent that just makes you happy to be alive. They inspire

perfume makers as well as poets. And then you have [the]

corpse flower, skunk cabbage, [and] voodoo lily. . They dare

us to come closer and have a look. When we do, we’re

rewardedwith the stench of rotting flesh or the pervasive odor

of skunk” [1]. Thus, perhaps there is moremeaning in a name.

PubMed queries of epithelial-to-mesenchymal transition

(EMT) and mesenchymal-to-epithelial transition (MET) will

provide the exact same results. Are they the same “rose?”

Undoubtedly not. However, the term “EMT” has been reduced

to indicating transitions in either direction, although clear

differences are present in the outcomes of each. Failing to

make the critical distinction between these 2 inverse

processes renders much of the “EMT” data sloppy and riddled

with misnomers. Compounding the problem, epithelial-

9.020.ncology, Department of Siego Health Sciences, 38153.

ier Inc. All rights reserved

mesenchymal interactions (EMIs) are also lumped together

with EMT andMET (Fig. 1). Do these distinctions reallymatter?

There is no disputing that paracrine EMIs exist [2].

However, in some circles, controversy persists about whether

EMT or MET actually exists in nature or whether they are

merely an in vitro epiphenomenom [3e5]. For the purposes of

this editorial, we will assume that all 3 processes can occur

outside of the tissue culture hood.

During human development, cellular transitions (i.e., EMT

and MET) and interactions (i.e., EMIs) dictate organogenesis.

Later in life, similar cell populations are involved in the

pathogenesis of organ fibrosis (i.e., renal, pancreatic, and

hepatic) and cancer. However, the processes of EMT, MET, and

EMIs are not equivalent. Each has distinct implications for

human disease, particularly carcinogenesis. Whether one is

a firm believer or an EMT/MET skeptic, a clearer delineation of

each term is necessary to help frame how scientists investi-

gate, manipulate, or debate the processes during cancer

initiation, progression, and metastasis. In vitro and in vivo

studies would suggest that stem cell signaling pathways

urgery, University of California, San Diego, Moores Cancer Center,55 Health Sciences Drive, Room 2313, Mail Code 0987, La Jolla, CA

.

Fig. 1 e Epithelialemesenchymal relations occur in 3

distinct manners. Epithelial cancer cells (blue) can undergo

transition to mesenchymal cells (green) during so-called

EMT. Conversely, mesenchymal stromal cells (green) can

undergo transition to epithelial cells (blue) during so-called

MET. Epithelial cancer cells and mesenchymal stromal

cells can also have paracrine interactions known as

tumorestroma interactions or EMIs. (Color version of

Figure is available online.)

j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 2 ( 2 0 1 3 ) 3 6e3 9 37

underlie or drive EM relations. In turn, this has led to the

development of targeted therapies to block these pathways.

However, by turning on or off such pathways (i.e., Hedgehog

[Hh], Wnt/b-catenin, Notch, and transforming growth factor-

b) during carcinogenesis, there could be unwanted conse-

quences. This is especially so if we incorrectly assume that

EMT equals MET. In the context of emerging cancer therapies,

understanding the differences in these processes is of great

importance. The following are partially factual case studies

that highlight the misnomers of EM relations and provide

clinical relevance for these distinctions.

1. Case Study 1dEMT

A 65-year-old woman presented with weight loss and left

upper quadrant pain. Computed tomography demonstrated

an 8-cm mass in the tail of the pancreas with innumerable

subcentimeter hepatic metastases. She underwent endo-

scopic ultrasonography with biopsy, which confirmed the

diagnosis of a pancreatic ductal adenocarcinoma (PDAC). She

underwent treatment with gemcitabine, but interval imaging

demonstrated disease progression. She began to inquire about

clinical trials. She was recruited to a phase II trial with a Notch

inhibitor that is thought to inhibit EMT. She had a transient

partial biochemical response. She ultimately died of her

disease.

If EMT is occurring as an early event in the process, trying to

prevent additional EMTmight not help the cause. EM relations

in cancer are similar to a mathematical vector in time. Thus,

themagnitude, direction, and time are all critical components.

The report by Krantz et al. [6] reviewed how EMT is associated

with PDAC invasion, metastasis, and chemotherapeutic

resistance. Several developmental signaling pathways such as

Notch and transforming growth factor-b are involved in this

process. For instance, Notch blockade with a g-secretase

inhibitor can slow tumor progression in mice and down-

regulate E-cadherin, an important event in EMT [7,8]. In the

oncologicclinical trials,mostnewagentsare initiallystudied in

the setting of advanced local disease or metastatic disease.

However, is this too late to think about targeting EMT? When

and where these drug candidates fail, is the next candidate

already set up for failure? Thus, should EMT be targeted only

early (i.e., before metastases develop) and/or should a second

anti-PDAC agent be considered for combination therapies to

avoid single-agent failure?

2. Case Study 2eMET

A 58-year-old man presented to the emergency department

with new right upper quadrant pain. Ultrasonography

demonstrated a largemass in the right hemiliver, and thiswas

subsequently confirmed on magnetic resonance imaging as

a 7.5-cm hypervascular mass in segments VII and VIII. No

evidence was found of metastatic disease. His a-fetoprotein

level was 450 ng/mL. Hepatitis serology demonstrated sero-

positivity for hepatitis C virus. He underwent right hemi-

hepatectomy for a hepatocellular carcinoma (HCC). At

surgery, the liver was fibrotic but not frankly cirrhotic. The

final pathologic examination demonstrated HCCwith grade 2-

4 hepatic fibrosis in the non-neoplastic liver. Two years later,

his a-fetoprotein level began to increase, and he was discov-

ered to have 4 new lesions in the liver remnant and progres-

sion of this underlying liver disease from hepatic fibrosis to

frank cirrhosis.

This case study provides an example of how MET, but not

EMT, occurs in the liver and shows how correct definition of

directionality is paramount. Within chronically injured livers,

there is an accumulation of senescent hepatocytes and hep-

atocytic progenitor cells [9e11]. It is postulated that these cells

might be the precursors to dysplastic liver nodules and liver

cancer. In the United States, HCC and cirrhosis often occur

secondary to hepatitis C virus [12e14], alcoholic liver disease

[13], and nonalcoholic fatty liver disease [15e18]. These

diseases pose a significant, and possibly additive, risk of

cirrhosis and HCC.

Patients with cirrhosis have an approximately 20% risk of

developing HCC within 5 years [19,20]. Both myofibroblastic

hepatic stellate cells (HSCs) and hepatic epithelial progenitors

accumulate in damaged livers. In injured organs, the ability to

distinguish between fibroblastic and epithelial cells is

j o u r n a l o f s u r g i c a l r e s e a r c h 1 8 2 ( 2 0 1 3 ) 3 6e3 938

sometimes difficult. To determine whether MET occurs in

adult liver cells, Sicklick et al. [21] analyzed the expression

profile of primary HSC, 2 HSC lines, and hepatic epithelial

progenitors. Notably, HSC markers were expressed by

epithelial liver progenitors in vitro. In addition, 1 HSC line

constitutively expressed typical epithelial progenitor mRNA,

and these markers were inducible in another HSC line. Addi-

tional work by Yang et al. [22] demonstrated that HSC could

undergo MET in the adult mouse liver to become epithelial

progenitors known as oval cells. Despite such knowledge,

effective treatment of cirrhosis is nonexistent, and the results

from most clinical trials for HCC therapy have been disap-

pointing [23,24].

We all know that patients with cirrhosis are at high risk of

developing HCC; however, no randomized clinical trial has

ever been performed that demonstrated an effective HCC

prevention therapy for patients with chronic liver disease. Are

we targeting thewrong cells? One can theorize that the drivers

of MET could be a novel target for treating both cirrhosis and

HCC if the HSCs can undergo MET to become preneoplastic

progenitors. Krantz et al. [6] rightly described that hepatocytes

do not appear to undergo EMT nor produce fibrosis according

to the results from genetic labeling studies [25]. However, they

failed to acknowledge the data suggesting that MET or EMIs

are important in hepatic fibrosis, cirrhosis, and carcinogenesis

[26]. Just as with amathematical vector, not only is magnitude

important, but so also is direction.

3. Case Study 3eEMIs

A 55-year-oldman developed new-onset obstructive jaundice.

Pancreas-protocol computed tomography demonstrated a

double duct sign with dilated pancreatic duct and common

bile duct. No evidence was seen for vascular involvement

or metastatic disease. He agreed to undergo pancreatic-

oduodenectomy. The gland was quite firm at surgery. He

recovered uneventfully. The final pathologic examination

demonstrated a stage pT2N0Mx pancreatic ductal adenocar-

cinoma with significant peritumoral fibrosis. He underwent

adjuvant treatment with a gemcitabine-based chemotherapy

regimen, which he tolerated splendidly. Nine months after

completing therapy, his imaging studies demonstrated

multiple new hepatic lesions concerning for metastatic

disease. He was recruited to a trial investigating the role of

a Hh signaling inhibitor in patients withmetastatic pancreatic

cancer. However, 8 months later, he died of his disease.

This is a scenario we have all seen play out time and again.

EM cross-talk is critical for some cellecell interactions.

Moreover, the timing of drug administration is just as

important as which agent to use, because targeting cancer-

associated fibroblasts (CAFs), which protect the primary

tumor, could be of a little utility if the primary tumor has

already been resected and micrometastases have spread to

the liver where other signaling pathways might be more

crucial. The stroma of PDAC is composed of deposited extra-

cellular matrix with CAFs. Work by Olive et al. [27] demon-

strated that inhibition of Hh signaling enhanced delivery of

gemcitabine in a transgenic mouse model of PDAC. They

found that epithelial tumor cells secrete Hh ligands and the

stromal CAFs express the Hh receptor and downstream

signaling components of the pathway. Such cellular organi-

zation allows for tumorestroma interactions or the so-called

epithelialemesenchymal interactions (EMIs). The tumors in

this model were poorly vascularized, just as is human PDAC,

because EMIs induced the survival and proliferation of Hh-

dependent CAFs, which served as a “moat” for the “cancer

kingdom.” Thus, “draining the moat” might not help. By

blocking Hh signaling with IPI-926, no effect was seen on the

tumor itself. However, this drug depleted the CAFs around the

tumor, leading to a transient increase in intratumoral vascular

density and intratumoral concentration of gemcitabine. This

led to transient disease stabilization. Clearly, there are

differences between EMIs and EMT or MET. Considering them

to be the same is counterproductive and might even be dele-

terious to patient outcomes if scientists and clinicians fail to

have a specific set of terminology to describe each process.

4. Conclusion

Emerging data from PDAC and other malignancies, such as

HCC, suggests that EMT, MET, and EMIs are all critical in

cancer progression. Although we have become more sophis-

ticated in our understanding of cancer, we have tried to force

mechanisms of disease into narrow categories such as “EMT.”

This has inadvertently minimized the roles and importance

of MET and/or EMIs. During cancer initiation and progression

and, ultimately, therapy, each epithelialemesenchymal pro-

cess might have different degrees of ebb and flow in time and

space. In turn, these should provoke clinicians and cancer

biologists alike to contemplate how these processes can be

appropriately harnessed to develop novel therapeutic agents.

We can reconsider “What’s in a name?” Perhaps there is

more meaning in a name than we sometimes appreciate. To

clinicians and scientists, correcting the misnomers of epi-

thelialemesenchymal relations in fibrosis and cancer would

be helpful for translating important scientific findings into

clinical successes.

Acknowledgments

I would like to thank Dr. David Tarin for his helpful discus-

sions and insight. I also thank Danielle Sandler for her critical

review of this report.

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