Idiopathic Pulmonary Fibrosis

An Altered Fibroblast Proliferation Linked to Cancer Biology

Carlo Vancheri1
1

Department of Clinical and Experimental Biomedicine, Section of Respiratory Diseases, Regional Center for Interstitial and Rare Lung Diseases,
University of Catania, Catania, Italy

The fibrotic process that characterizes idiopathic pulmonary fibrosis

(IPF) is commonly considered the result of a recurrent injury to the
alveolar epithelium followed by an uncontrolled proliferation of
fibroblasts. However, based on considerable scientific evidence, it
has been recently hypothesized that IPF might be considered a neoproliferative disorder of the lung because this disease exhibits
several pathogenic features similar to cancer. Indeed, epigenetic
and genetic abnormalities, altered cell-to-cell communications,
uncontrolled proliferation, and abnormal activation of specific
signal transduction pathways are biological hallmarks that characterize the pathogenesis of IPF and cancer. IPF remains a disease
marked by a survival of 3 years, and little therapeutic progress has
been made in the last few years, underlining the urgent need to
improve research and to change our approach to the comprehension
of this disease. The concept of IPF as a cancer-like disease may be
helpful in identifying new pathogenic mechanisms that can be
borrowed from cancer biology, potentially leading to different and
more effective therapeutic approaches. Such vision will hopefully
increase the awareness of this disease among the public and the
scientific community.
Keywords: lung fibrosis; cancer; fibroblasts; signal transduction pathways

According to the generally accepted pathogenic hypothesis, the

fibrotic changes observed in idiopathic pulmonary fibrosis (IPF)
are the result of a recurrent, long-lasting injury to the alveolar
epithelium followed by an uncontrolled and unrelenting proliferation of fibroblast-like cells termed myofibroblasts (1).
Myofibroblasts invade the interstitial and alveolar spaces and
cause progressive distortion of the pulmonary architecture that
makes gas exchange difficult if not impossible. However, it has
been recently reported that IPF exhibits several pathogenic
features similar to cancer, thus supporting the hypothesis that
this disease might be considered a neoproliferative disorder of
the lung (2). In favor of this argument are the findings of Cool
and colleagues, who described for the first time that fibroblast
foci, the paradigmatic histological lesions of IPF, are interconnected, forming a reticulum that infiltrates the lung parenchyma
similar to a neoplasm that invades the surrounding tissue (3).
Indeed, the biological behavior of IPF may resemble some form
of cancer, such as desmoid tumors. These are fibroblastic neoplasms that may be locally invasive but are incapable of metastasizing (4). Moreover, the described absence of monoclonality
among the myofibroblasts forming the foci do not necessarily
exclude the neoproliferative nature of IPF because there is
ample evidence that many cancers may be polyclonal (57).
Fibroblasts within the foci are activated and possess a number
of functional features that are similar to cancer cells: Epigenetic
(Received in original form March 10, 2012; accepted in final form May 10, 2012)
Correspondence and requests for reprints should be addressed to Carlo Vancheri
M.D., Ph.D., Regional Center for Interstitial and Rare Lung Diseases, Department
of Clinical and Experimental Biomedicine, Section of Respiratory Diseases, University of Catania, Via S. Sofia 78., 95123, Catania, Italy. E-mail: [email protected]
Proc Am Thorac Soc Vol 9, Iss. 3, pp 153157, Jul 15, 2012
Copyright 2012 by the American Thoracic Society
DOI: 10.1513/pats.201203-025AW
Internet address: www.atsjournals.org

and genetic abnormalities, altered cell-to-cell communications,

uncontrolled proliferation, and abnormal activation of specific
signal transduction pathways are biological hallmarks that characterize these cells and the pathogenesis of IPF and cancer
(Table 1). The vision of IPF as a neoproliferative disorder of
the lung, notwithstanding the need for more comprehensive investigation, may add new insights to the pathogenesis of IPF
borrowed from cancer biology. Therefore, new and different
therapeutic approaches for this disease could be offered.

EPIGENETIC AND GENETIC ABNORMALITIES

Epigenetic alterations in response to environmental exposure,
tobacco smoke, diet, and ageing are commonly described in cancer where the methylation of tumor suppressor genes and the
hypomethylation of oncogenes have an important role in carcinogenesis (8). Recent evidence suggests that changes in phenotype and gene expression without alterations in DNA sequence
may contribute to the pathogenesis of IPF (9). Rabinovich and
colleagues have recently shown that global methylation patterns
in IPF are different compared with control tissues and are in
some respect similar to lung cancer (10). In addition, there is
evidence to show that in lung tissue from patients with IPF, due
to the hypermethylation of the Thy-1 promoter region, there is
a reduced expression of the glycoprotein Thy-1, which is normally expressed by fibroblasts (11, 12). In IPF the loss of this
molecule is linked to the transformation of fibroblasts into myofibroblasts within fibroblast foci, whereas in cancer it is associated with a more invasive behavior of the disease. Moreover,
it has been shown that the pharmacological inhibition of the
methylation of the Thy-1 gene is able to restore the expression
of Thy-1, suggesting a novel pathogenic mechanism of lung
fibrosis and possibly a new therapeutic approach for this disease
(12). Proper genetic mutations of tumor suppressor genes involved in the control of cell proliferation and apoptosis, such as
p53 and fragile histidine triade, have been described in IPF and
specifically in the peripheral honeycomb areas characteristic of
the disease, whereas more specific mutations, such as microsatellite instability and loss of heterozygosity, have been observed
in about 50% of patients with IPF. These genetic alterations are
considered key factors in the birth and progression of several
cancers, including lung, gastric, and colorectal cancer (1318).
Other mutations commonly associated with cancer initiation
and development, such as telomere shortening and telomerase
expression, have been described in familial and sporadic IPF
(1922). More recently, the abnormal expression of microRNAs
has been associated with the pathogenesis of cancer and IPF.
MicroRNAs are short, nonprotein coding RNAs that are involved in the regulation of different processes related to carcinogenesis, such as tumor growth, invasion, and metastasis.
Moreover, there is much evidence that microRNAs in cancer
may represent a diagnostic and prognostic marker as well as
a possible therapeutic target (23). Recently, it has been shown
that about 10% of microRNAs are abnormally expressed in
IPF. Some of them, such as let-7, mir-29, mir-30, and mir-200,
are significantly down-regulated, whereas mir-155 and mir-21

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2012

TABLE 1. PATHOGENIC SIMILARITIES BETWEEN IDIOPATHIC PULMONARY FIBROSIS AND CANCER

Genetic alterations
Tumor suppressor gene mutations
Altered telomerase expression
Abnormal expression of microRNAs
Epigenetic alterations
Hypermethylation Thy gene
Uncontrolled proliferation
Self-sufficiency in growth signals
Insensitivity to inhibitory signals
Evasion of apoptosis
Altered cell-to-cell communication
Tissue Invasion
Myofibroblast origin and recruitment
Myofibroblast infiltrative ability
Expression of invasive molecules
Signal transduction pathways
Activation of Wnt/b-catenin pathway
Activation of PI3K/AKT pathway

P53, FHIT, microsatellite instability, loss of heterozygosity

Telomere shortening
miR-21, miR-200, let-7d

Myofibroblast differentiation

Autocrine TGF-b production

Reduced expression of prostanoid receptors
Reduce expression of TNFR1
Reduced CX43 expression

Aggressive myofibroblast behavior

Expression of HSP-27, laminin, fascin

Fibroblast activation, proliferation, and differentiation

are up-regulated. In both cases, their changes are linked to

epithelial-mesenchymal transition (EMT) induction, regulation
of apoptosis, ECM remodeling, and the modulation of fibrosis
in the bleomycin model of pulmonary fibrosis (2428). Considering this, Yang and colleagues have shown that the miR-200
family members are down-regulated in the lung of mice with
bleomycin-induced fibrosis and that restoration of miR-200 expression can reverse lung fibrosis, thus inhibiting TGF-b1induced
epithelialmesenchymal transition (29). Another study has shown
that the up-regulation of miR-21 was related to the fibrotic damage induced by bleomycin, whereas the administration of miR21
antisense nucleotides reduced the profibrotic effect exerted by
bleomycin even when the treatment was started 7 days after
bleomycin (30). The microRNAs studied in IPF increase the
expression of TGF-b, which causes their aberrant expression,
thus creating a sort of vicious circle. Recently, a combined analysis of mRNA and miRNA has shown different genetic subsets
in patients with different types and stages of interstitial lung
diseases and has revealed, specifically in advanced lung fibrosis,
an involvement of the TGF-b1, Wnt, sonic hedgehog, p53, vascular endothelial growth factor, EMT, and apoptosis pathways
(25). As such, miRNAs may be considered a critical point of
a number of molecular and signaling networks involved in cancer and fibrosis. MicroRNA, mRNA, and particularly cell-free
DNA are also elevated in the blood of patients with cancer in
comparison with normal subjects. Cell-free DNA often presents
the same genetic and epigenetic changes observed in the DNA
of the related cancer and for this reason is considered a potential diagnostic and prognostic biomarker of cancer (31). Casoni
and colleagues showed significantly higher levels of free circulating DNA in patients affected by IPF compared with healthy
subjects and other fibrotic diffuse lung diseases, such as nonspecific pulmonary fibrosis. This suggests a role for cell-free
DNA in discriminating IPF from other fibrotic lung disorders
(32).

ALTERED CELL-TO-CELL COMMUNICATIONS

Gap junctions are transmembrane channels formed by aggregates of proteins (termed connexins) that, by connecting the
cytoplasm of adjacent cells, allow the passage of ions, small
molecules, and second messengers. This allows rapid intercellular communication that results in the metabolic and electrical
coupling of cells and ultimately in the synchronization of activities such as proliferation and tissue repair (33). In the lung,
among the different connexins expressed, Cx43 plays a central
role in the regulation of intercellular communications. Cx43 is

particularly expressed by lung fibroblasts and is considered the

major connexin functionally connecting airway, alveolar, and
endothelial cells (34). There is much evidence to show that
cancer is often associated with a diminished expression of connexins and with the reduction of gap junctional intercellular
communication (35). Lung cancer cell lines from mouse and
human lung carcinoma have low or absent levels of Cx43 expression, and the deletion of the Cx43 gene results in higher
susceptibility to lung adenoma formation in mice after urethane
administration (36). On the contrary, the transfection of human
lung carcinoma cell lines with Cx43 cDNA induces in these cells
a reduced growth rate in vitro and in vivo (37). In gastric cancer,
the expression of Cx43 is directly related to the degree of differentiation of cancer cells: the less differentiated and aggressive the cancer, the lower the expression of Cx43 (38). Cx43 is
also the most represented connexin on fibroblasts, and there is
evidence showing its involvement in the reparative process that
takes place during wound healing. The down-regulation, with
antisense oligodeoxynucleotides of the expression of this connexin, increases cell proliferation and migration of keratinocytes and fibroblasts, accelerating wound repair at skin wound
sites, whereas the reduction of Cx43, in an in vitro model of fibroblast wound healing, leads to increased expression of TGF-b, collagen production, and myofibroblast differentiation and hence to
a faster healing process. The increased fibroblast proliferation and
differentiation induced by Cx43 down-regulation may accelerate
wound healing, although in different contexts it may also be responsible for the loss of fibroblast proliferative control that characterizes abnormal repair and/or fibrosis. Indeed, fibroblasts from
keloids and hypertrophic scars, compared with normal skin tissue,
express significantly lower levels of Cx43 (39). We have shown
that, in primary lung fibroblasts from patients with IPF, there is
a reduced expression of Cx43, and, using a dye-loading technique,
we assessed gap junctional activity, showing a reduced gap junctional intercellular communication in fibrotic fibroblasts compared with normal cells. The reduced cell-to-cell communication
described in IPF fibroblasts is similar to what has been described
in cancer cells and may give an explanation for the release from
the restraint of contact inhibition and uncontrolled proliferation
that is present in both these diseases (40).

UNCONTROLLED PROLIFERATION: THE ROLE

OF MYOFIBROBLASTS
Although several studies have suggested that myofibroblasts
mainly derive from resident lung fibroblasts, the origin of
these cells is still controversial in cancer and IPF. In pulmonary

Vancheri: IPF: An Altered Fibroblast Proliferation Linked to Cancer

fibrosis, epithelial cells surrounding fibroblast foci express epithelial and mesenchymal markers, suggesting that EMT occurs
in those areas of lung tissue and that this process may play an
active role in lung fibrogenesis (41, 42). EMT is also a crucial
feature of many cancers and is involved in the early stages of
carcinogenesis and cancer cell invasion (43). Another important
source of lung myofibroblasts are extrapulmonary progenitor
cells termed fibrocytes. These are bone marrowderived cells
that coexpress markers of fibroblasts and hematopoietic cells.
Several reports have shown that some of the myofibroblasts
forming the tumor stroma are derived from these cells and
may have a role in cancer progression, whereas the increased
number of fibrocytes observed in IPF has suggested a direct
involvement of these cells in the fibrotic process (4448). Regardless of their origin, cancer-associated fibroblasts produce
a number of different mediators, such as metalloproteinases
and growth factors, that directly promote cancer progression
(49). Similarly to cancer, myofibroblasts in IPF may sustain
their own growth by producing, in an autocrine way, several
cytokines, including the fibrogenic TGF-b, thus partially losing
the ability to produce the antifibrotic PGE2. The diminished
ability of these cells to express the E prostanoid receptor 2
causes a further reduction of their response to the inhibitory
activity exerted by PGE2, such as collagen expression and
TGF-binduced transition of fibroblasts into myofibroblasts
(50, 51). TGF-b also protects myofibroblasts from apoptosis,
likely caused by the modified response to TNF-a, due to a reduced expression of the TNF receptor 1, which is known to
mediate growth inhibition and death events (52). In primary
and metastatic cancers, TGF-b produced by cancer-derived
epithelial cells is responsible for the emergence of myofibroblasts at the invasive front of the tumor. These cells produce
additional TGF-b, other inflammatory mediators, and metalloproteinases that may facilitate cancer invasiveness by breaking
up the basement membrane of the surrounding tissues. Indeed,
cancer progression has been related to the expression of TGF-b
and metalloproteinases expressed by cancer cells, and their increased levels are considered a negative prognostic factor of
survival in many cancers, including lung cancer (53). Tumor progression also depends on the expression of a series of molecules
that are able to facilitate cancer invasion. Laminin, for example,
often coexpressed with a protease involved in tumor cell invasion
termed matrilysin, is a component of the extracellular matrix
expressed at the invasive front of many different cancers. It stimulates migration and tumor progression to the extent that its overexpression is considered a marker of invasiveness often associated
with poor prognosis. Other molecules expressed by cancer cells
and associated with invasiveness, poor prognosis, and resistance
to treatment are heat shock protein (HSP)27 and fascin. HSP27
prevents cell apoptosis by interfering at different levels in the
programmed cell death process. Fascin is a protein involved in cell
matrix adhesion and migration that is strongly up-regulated in
many carcinomas, particularly at the advancing edge of the cancer.
Its overexpression is also related to poor patient prognosis (5457).
In IPF, Chilosi and colleagues have shown that epithelial cells
surrounding fibroblast foci express large amounts of laminin, fascin, and HSP27 (58). Cells expressing these molecules were exclusively bronchiolar basal cells layered between luminal epithelial
cells on one side and myofibroblasts on the other. This three-layer
arrangement of negative-positive-negative cells was compared
with a sandwich and these areas of lung tissue termed sandwich
fibroblast-foci by the same authors. The expression of molecules
so involved in cell migration and invasion in bronchiolar basal cells
adjacent to myofibroblasts while facing the luminal epithelium is
reminiscent of what has been described in cancer where these
molecules are expressed at the invasive front of carcinomas (53).

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ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS

Several reports have shown that the regulation of the expression
of molecules such as matrilysin, laminin, and cyclin-D1 is
entrusted by the Wnt/b-catenin signaling pathway. An aberrant
activation of this signaling pathway has been observed in several
human cancers, including lung cancer and mesothelioma (59),
and more recently in different fibroproliferative disorders of the
liver and kidney (60, 61). Chilosi and colleagues have shown
that the Wnt/b-catenin pathway is strongly activated in IPF lung
tissues, as demonstrated by the presence of an intense immunoreactivity for b-catenin and a contemporary expression of high
levels of two downstream genes of the Wnt/b-catenin pathway,
cyclin-D1 and matrilysin (62). In this disease, in addition to the
canonical activation, the Wnt pathway may be activated by the
fibrogenic cytokine TGF-b. Considering this, we have recently
demonstrated that TGF-b via the phosphorylation of ERK1/2
activates the Wnt pathway in lung fibroblasts, inhibiting GSK-3b
activity, thus promoting the cytosolic accumulation and subsequent nuclear translocation of b-catenin (63). The transcription
of ERK1/2 target gene, induced by TGF-b, could also lead to
a secondary activation of other signaling pathways that may regulate cell proliferation and apoptosis. Failure to activate the apoptotic program may represent an important step in the abnormal
repair that takes place in lung fibrosis, in carcinogenesis, and in
the insurgence of drug resistance in cancer cells. Survival signals
induced by several receptors are often mediated by the PI3K/
AKT pathway. In this context it has been shown that the transfection of fibroblasts with active PI3K increases the phosphorylation of AKT, thereby protecting these cells from apoptosis
(64). Activated AKT also modulates the function of numerous
substrates involved in the regulation of cell survival, cell cycle
progression, and cellular growth, all events crucially involved in
the pathogenesis of cancer where the overexpression of phosphorylated AKT has been directly linked to a poor prognosis
(65). In addition, in fibroblasts isolated from patients with IPF,
a pathological activation of AKT has been shown, and its phosphorylation has been related to fibroblast proliferation and differentiation into myofibroblasts. In a recent study, we have shown
that LY294002, an inhibitor of PI3K, inhibits AKT phosphorylation and significantly reduces cell proliferation, a-smooth muscle
actin expression, and collagen production in lung fibroblasts activated by TGF-b, thus demonstrating the centrality of the PI3K/
AKT pathway in lung fibroblast proliferation and differentiation.
Moreover, we have demonstrated that, in addition to the ubiquitously expressed PI3K p110a and p110b, human lung fibroblasts
express the p110D and p110g isoforms. By using specific pharmacological inhibitors of the single PI3K isoforms and selective
gene knocking by siRNAs, we also demonstrated a major role
of p110g and p110a in TGF-binduced fibroblast proliferation
and differentiation, suggesting that specific PI3K isoforms might be
considered significant new targets for the treatment of IPF (66).
Another downstream mediator of the profibrotic activities played
by TGF-b, such as a-SMA expression and collagen I production, is
endothelin (ET)-1 (67). In light of this observation, the antagonism
of the ET-1 receptors ETA and ETB has been used as a potential
treatment for IPF. ET-1 is produced not only by stromal but also
by cancer cells, consequently activating several signaling pathways,
such as AKT, MAPK, and PKC. These pathways are fully involved
in the regulation of cell proliferation, migration, invasion, angiogenesis, and apoptosis, hence supporting the evidence showing the
role played by ET-1 in promoting the progression of several different cancers, such as prostatic, colorectal, breast, lung, bladder,
and brain cancer. ET-1 has been proposed as a negative prognostic
marker in some cancers, and the blockade of ET-1 receptors has
been found to enhance the efficacy of anticancer therapy (68).

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CONCLUSIONS
The recognition of cancer as a potentially fatal disease of unknown origin is widespread, and the need for sustaining cancer
research is accepted at any level of public opinion. This has led to
an incredible improvement in the diagnostic and therapeutic
strategies against this disease over the last 30 years. Although
the mortality rate of IPF is worse than for the majority of cancers,
the severity of this disease is still underestimated, its diagnosis is
often made late, there is a lack of diagnostic and prognostic biomarkers, and the present knowledge of the pathogenesis is not
sufficient to develop treatment strategies capable of stopping
or reverting the disease. The existence of a pathogenic link between IPF and cancer is based in part on circumstantial evidence
because lung fibrosis and cancer have been associated with similar etiologic agents, such as cigarette smoking, viral infections,
occupational exposition, and environmental agents. However, an
increasing number of biological and pathogenic analogies between IPF and cancer have been recently identified, including
epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled cell proliferation, and abnormal activation of specific signal transduction pathways. The concept of
IPF as a neoproliferative disorder of the lung may help the urgent need for a better understanding of the pathogenesis of IPF
by taking advantage of the vast knowledge that exists of cancer
biology. It may also have significance well beyond the shared biological and pathogenic characteristics of the two diseases, increasing the awareness of this devastating condition among
the general public, patients, and health operators.

14.

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Author disclosures are available with the text of this article at www.atsjournals.org.

References
1. Selman M, King TE, Pardo A. Idiopathic pulmonary fibrosis: prevailing
and evolving hypotheses about its pathogenesis and implications for
therapy. Ann Intern Med 2001;134:136151.
2. Vancheri C, Failla M, Crimi N, Raghu G. Idiopathic pulmonary fibrosis:
a disease with similarities and links to cancer biology. Eur Respir J
2010;35:496504.
3. Cool CD, Groshong SD, Rai PR, Henson PM, Stewart JS, Brown KK.
Fibroblast foci are not discrete sites of lung injury or repair: the fibroblast reticulum. Am J Respir Crit Care Med 2006;174:654658.
4. Kotiligam D, Lazar AJ, Pollock RE, Lev D. Desmoid tumor: a disease
opportune for molecular insights. Histol Histopathol 2008;23:117126.
5. Davidsson J, Paulsson K, Johansson B. Multicolor fluorescence in situ
hybridization characterization of cytogenetically polyclonal hematologic malignancies. Cancer Genet Cytogenet 2005;163:180183.
6. Parsons BL. Many different tumor types have polyclonal tumor origin:
evidence and implications. Mutat Res 2008;659:232247.
7. Lyons JG, Lobo E, Martorana AM, Myerscough MR. Clonal diversity in
carcinomas: its implications for tumour progression and the contribution made to it by epithelial-mesenchymal transitions. Clin Exp
Metastasis 2008;25:665677.
8. Shenker N, Flanagan JM. Intragenic DNA methylation: implications of
this epigenetic mechanism for cancer research. Br J Cancer 2012;106:
248253.
9. Kass DJ, Kaminski N. Evolving genomic approaches to idiopathic pulmonary fibrosis: moving beyond genes. Clin Transl Sci 2011;4:372379.
10. Rabinovich E, Kapetanaki M, Steinfeld I, Gibson KF, Pandit K, Yu G,
Yakhini Z, Kaminsky N. Global methylation patterns in idiopathic
pulmonary fibrosis. PLoS ONE 2012;7:e33770.
11. Sanders YY, Kumbla P, Hagood JS. Enhanced myofibroblastic differentiation and survival in Thy-1(-) lung fibroblasts. Am J Respir Cell
Mol Biol 2007;36:226235.
12. Sanders YY, Pardo A, Selman M, Nuovo GJ, Tollefsbol TO, Siegal GP,
Hagood JS. Thy-1 promoter hypermethylation: a novel epigenetic
pathogenic mechanism in pulmonary fibrosis. Am J Respir Cell Mol
Biol 2008;39:610618.
13. Kuwano K, Kunitake R, Kawasaki M, Nomoto Y, Hagimoto N,
Nakanishi Y, Hara N. P21Waf1/Cip1/Sdi1 and p53 expression in

23.
24.

25.
26.

27.

28.

29.

30.

31.
32.

33.
34.

35.

2012

association with DNA strand breaks in idiopathic pulmonary fibrosis.

Am J Respir Crit Care Med 1996;154:477483.
Saed GM, Ladin D, Olson J, Han X, Hou Z, Fivenson D. Analysis of p53
gene mutations in keloids using polymerase chain reaction-based
single-strand conformational polymorphism and DNA sequencing.
Arch Dermatol 1998;134:963967.
Lok SS, Stewart JP, Kelly BG, Hasleton PS, Egan JJ. Epstein-Barr virus and
wild p53 in idiopathic pulmonary fibrosis. Respir Med 2001;95:787791.
Hojo S, Fujita J, Yamadori I, Kamei T, Yoshinouchi T, Ohtsuki Y,
Okada H, Bandoh S, Yamaji Y, Takahara J, et al. Heterogeneous
point mutations of the p53 gene in pulmonary fibrosis. Eur Respir J
1998;12:14041408.
Uematsu K, Yoshimura A, Gemma A, Mochimaru H, Hosoya Y,
Kunugi S, Matsuda K, Seike M, Kurimoto F, Takenaka K, et al.
Aberrations in the fragile histidine triad (FHIT) gene in idiopathic
pulmonary fibrosis. Cancer Res 2001;61:85278533.
Demopoulos K, Arvanitis DA, Vassilakis DA, Siafakas NM, Spandidos
DA. MYCL1, FHIT, SPARC, p16(INK4) and TP53 genes associated
to lung cancer in idiopathic pulmonary fibrosis. J Cell Mol Med 2002;
6:215222.
Cronkhite JT, Xing C, Raghu G, Chin KM, Torres F, Rosenblatt RL,
Garcia CK. Telomere shortening in familial and sporadic pulmonary
fibrosis. Am J Respir Crit Care Med 2008;178:729737.
Liu T, Chung MJ, Ullenbruch M, Yu H, Jin H, Hu B, Choi YY, Ishikawa
F, Phan SH. Telomerase activity is required for bleomycin-induced
pulmonary fibrosis in mice. J Clin Invest 2007;117:38003809.
Tsakiri KD, Cronkhite JT, Kuan PJ, Xing C, Raghu G, Weissler JC,
Rosenblatt RL, Shay JW, Garcia CK. Adult-onset pulmonary fibrosis
caused by mutations in telomerase. Proc Natl Acad Sci USA 2007;104:
75527557.
Diaz de Leon A, Cronkhite JT, Katzenstein AL, Godwin JD, Raghu G,
Glazer CS, Rosenblatt RL, Girod CE, Garrity ER, Xing C, et al. Telomere lengths, pulmonary fibrosis and telomerase (TERT) mutations.
PLoS ONE 2010;5:111.
Lovat F, Valeri N, Croce CM. microRNAs in the pathogenesis of cancer.
Semin Oncol 2011;38:724733.
Oak SR, Murray L, Herath A, Sleeman M, Anderson I. A micro RNA
processing defect in rapidly progressing idiopathic pulmonary fibrosis.
PLoS ONE 2011;6:e21253.
Pandit KV, Milosevic J, Kaminski N. MicroRNAs in idiopathic pulmonary fibrosis. Transl Res 2011;157:191199.
Cushing L, Kuang P, Qian J, Shao F, Wu J, Little F, Thannickal VJ,
Cardoso WV, Lu J. miR-29 is a major regulator of genes associated with
pulmonary fibrosis. Am J Respir Cell Mol Biol 2011;45:287294.
Pottier N, Maurin T, Chevalier B, Puisse M, Lebrigand K, RobbeSermesant K, Bertero T, Lino Cardenas CL, Courcot E, Rios G, et al.
Identification of keratinocyte growth factor as a target of microRNA155 in lung fibroblasts: implication in epithelial-mesenchymal interactions. PLoS ONE 2009;4:e6718.
Pandit KV, Corcoran D, Yousef H, Yarlagadda M, Tzouvelekis A,
Gibson KF, Konishi K, Yousem SA, Singh M, Handley D, et al. Inhibition and role of let-7d in idiopathic pulmonary fibrosis. Am J
Respir Crit Care Med 2010;182:220229.
Yang S, Banerjee S, de Freitas A, Sanders YY, Ding Q, Matalon S,
Thannickal VJ, Abraham E, Liu G. Participation of miR-200 in pulmonary fibrosis. Am J Pathol 2012;180:484493.
Liu G, Friggeri A, Yang Y, Milosevic J, Ding Q, Thannickal VJ, Kaminsky
N, Abraham E. miR-21 mediates fibrogenic activation of pulmonary
fibroblasts and lung fibrosis. J Exp Med 2010;207:15891597.
Schwarzenbach H, Hoon DS, Pantel K. Cell-free nucleic acids as biomarkers in cancer patients. Nat Rev Cancer 2011;11:426437.
Casoni GL, Ulivi P, Mercatali L, Chilosi M, Tomassetti S, Romagnoli M,
Ravaglia C, Gurioli C, Zoli W, Silvestrini R, et al. Increased levels of
free circulating DNA in patients with idiopathic pulmonary fibrosis.
Int J Biol Markers 2010;25:229235.
Losa D, Chanson M, Crespin S. Connexins as therapeutic targets in lung
disease. Expert Opin Ther Targets 2011;15:9891002.
Johnson LN, Koval M. Cross-talk between pulmonary injury, oxidant
stress, and gap junctional communication. Antioxid Redox Signal
2009;11:355367.
Cesen-Cummings K, Fernstrom MJ, Malkinson AM, Ruch RJ. Frequent
reduction of gap junctional intercellular communication and connexin43

Vancheri: IPF: An Altered Fibroblast Proliferation Linked to Cancer

36.

37.

38.

39.

40.

41.
42.

43.

44.

45.

46.

47.

48.
49.

50.

51.

52.

expression in human and mouse lung carcinoma cells. Carcinogenesis

1998;19:6167.
Avanzo JL, Mesnil M, Hernandez-Blazquez FJ, Mackowiak II, Mori
CM, da Silva TC, Oloris SC, Garate AP, Massironi SM, Yamasaki
H, et al. Increased susceptibility to urethane-induced lung tumors in
mice with decreased expression of connexin43. Carcinogenesis 2004;
25:19731982.
Zhang ZQ, Zhang W, Wang NQ, Bani-Yaghoub M, Lin ZX, Naus CC.
Suppression of tumorigenicity of human lung carcinoma cells after
transfection with connexin43. Carcinogenesis 1998;19:18891894.
Tang B, Peng ZH, Yu PW, Yu G, Qian F. Expression and significance of
Cx43 and E-cadherin in gastric cancer and metastatic lymph nodes.
Med Oncol 2011;28:502508.
Mori R, Power KT, Wang CM, Martin P, Becker DL. Acute downregulation of connexin43 at wound sites leads to a reduced inflammatory
response, enhanced keratinocyte proliferation and wound fibroblast
migration. J Cell Sci 2006;119:51935203.
Trovato-Salinaro A, Trovato-Salinaro E, Failla M, Mastruzzo C,
Tomaselli V, Gili E, Crimi N, Condorelli DF, Vancheri C. Altered
intercellular communication in lung fibroblast cultures from patients
with idiopathic pulmonary fibrosis. Respir Res 2006;7:122.
Willis BC, du Bois RM, Borok Z. Epithelial origin of myofibroblasts
during fibrosis in the lung. Proc Am Thorac Soc 2006;3:377382.
Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN,
Sheppard D, Chapman HA. Alveolar epithelial cell mesenchymal
transition develops in vivo during pulmonary fibrosis and is regulated by
the extracellular matrix. Proc Natl Acad Sci USA 2006;103:1318013185.
De Wever O, Pauwels P, De Craene B, Sabbah M, Emami S, Redeuilh
G, Gespach C, Bracke M, Berx G. Molecular and pathological signatures of epithelial-mesenchymal transitions at the cancer invasion
front. Histochem Cell Biol 2008;130:481494.
Phillips RJ, Burdick MD, Hong K, Lutz MA, Murray LA, Xue YY,
Belperio JA, Keane MP, Strieter RM. Circulating fibrocytes traffic to
the lungs in response to CXCL12 and mediate fibrosis. J Clin Invest
2004;114:438446.
Mehrad B, Burdick MD, Zisman DA, Keane MP, Belperio JA, Strieter
RM. Circulating peripheral blood fibrocytes in human fibrotic interstitial lung disease. Biochem Biophys Res Commun 2007;353:104108.
Rojas M, Xu J, Woods CR, Mora AL, Spears W, Roman J, Brigham KL.
Bone marrow-derived mesenchymal stem cells in repair of the injured
lung. Am J Respir Cell Mol Biol 2005;33:145152.
Direkze NC, Hodivala-Dilke K, Jeffery R, Hunt T, Poulsom R, Oukrif D,
Alison MR, Wright NA. Bone marrow contribution to tumor-associated
myofibroblasts and fibroblasts. Cancer Res 2004;64:84928495.
Quan TE, Cowper SE, Bucala R. The role of circulating fibrocytes in
fibrosis. Curr Rheumatol Rep 2006;8:145150.
Desmoulie`re A, Guyot C, Gabbiani G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int J Dev Biol
2004;48:509517.
McAnulty RJ, Hernandez-Rodriguez NA, Mutsaers SE, Coker RK,
Laurent GJ. Indomethacin suppresses the anti-proliferative effects of
transforming growth factor-beta isoforms on fibroblast cell cultures.
Biochem J 1997;321:639643.
Moore BB, Ballinger MN, White ES, Green ME, Herrygers AB, Wilke
CA, Toews GB, Peters-Golden M. Bleomycin-induced E prostanoid
receptor changes alter fibroblast responses to prostaglandin E2.
J Immunol 2005;174:56445649.
Vancheri C, Sortino MA, Tomaselli V, Mastruzzo C, Condorelli F,
Bellistr G, Pistorio MP, Canonico PL, Crimi N. Different expression

157

53.

54.

55.

56.

57.

58.

59.
60.
61.
62.

63.

64.

65.

66.

67.

68.

of TNF-alpha receptors and prostaglandin E(2)Production in normal

and fibrotic lung fibroblasts: potential implications for the evolution
of the inflammatory process. Am J Respir Cell Mol Biol 2000;22:628
634.
Micke P, Ostman A. Tumour-stroma interaction: cancer-associated
fibroblasts as novel targets in anti-cancer therapy? Lung Cancer
2004;45:S163S175.
Moriya Y, Niki T, Yamada T, Matsuno Y, Kondo H, Hirohashi S. Increased expression of laminin-5 and its prognostic significance in lung
adenocarcinomas of small size: an immunohistochemical analysis of
102 cases. Cancer 2001;91:11291141.
Masaki T, Sugiyama M, Matsuoka H, Abe N, Izumisato Y, Sakamoto A,
Atomi Y. Coexpression of matrilysin and laminin-5 gamma2 chain
may contribute to tumor cell migration in colorectal carcinomas. Dig
Dis Sci 2003;48:12621267.
Garrido C, Schmitt E, Cande C, Vahsen N, Parcellier A, Kroemer G.
HSP27 and HSP70: potentially oncogenic apoptosis inhibitors. Cell
Cycle 2003;2:579584.
Pelosi G, Pastorino U, Pasini F, Maissoneuve P, Fraggetta F, Iannucci A,
Sonzogni A, De Manzoni G, Terzi A, Durante E, et al. Independent
prognostic value of fascin immunoreactivity in stage I nonsmall cell
lung cancer. Br J Cancer 2003;88:537547.
Chilosi M, Zamo A, Doglioni C, Reghellin D, Lestani M, Montagna L,
Pedron S, Ennas MG, Cancellieri A, Murer B, et al. Migratory marker
expression in fibroblast foci of idiopathic pulmonary fibrosis. Respir
Res 2006;7:95.
Mazieres J, He B, You L, Xu Z, Jablons DM. Wnt signaling in lung
cancer. Cancer Lett 2005;222:110.
Bowley E, OGorman DB, Gan BS. Beta-catenin signaling in fibroproliferative disease. J Surg Res 2007;138:141150.
Surendran K, McCaul SP, Simon TC. A role for Wnt-4 in renal fibrosis.
Am J Physiol Renal Physiol 2002;282:F431F441.
Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, Pedron
S, Bertaso M, Scarpa A, Murer B, et al. Aberrant Wnt/beta-catenin
pathway activation in idiopathic pulmonary fibrosis. Am J Pathol
2003;162:14951502.
Caraci F, Gili E, Calafiore M, Failla M, La Rosa C, Crimi N, Sortino
MA, Nicoletti F, Copani A, Vancheri C. TGF-beta1 targets the GSK3beta/beta-catenin pathway via ERK activation in the transition of
human lung fibroblasts into myofibroblasts. Pharmacol Res 2008;57:
274282.
Tian B, Lessan K, Kahm J, Kleidon J, Henke C. Beta 1 integrin regulates
fibroblast viability during collagen matrix contraction through a
phosphatidylinositol 3-kinase/Akt/protein kinase B signaling pathway. J Biol Chem 2002;277:2466724675.
Tang JM, He QY, Guo RX, Chang XJ. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer
confers poor prognosis. Lung Cancer 2006;51:181191.
Conte E, Fruciano M, Fagone E, Gili E, Caraci F, Iemmolo M, Crimi N,
Vancheri C. Inhibition of PI3K prevents the proliferation and differentiation of human lung fibroblasts into myofibroblasts: the role of
class I P110 isoforms. PLoS ONE 2011;6:e24663.
Shi-wen X, Kennedy L, Renzoni EA, Bou-Gharios G, du Bois RM, Black
CM, Denton CP, Abraham DJ, Leask A. Endothelin is a downstream
mediator of profibrotic responses to transforming growth factor beta in
human lung fibroblasts. Arthritis Rheum 2007;56:41894194.
Bagnato A, Spinella F, Rosano L. The endothelin axis in cancer: the
promise and the challenges of molecularly targeted therapy. Can J
Physiol Pharmacol 2008;86:473484.