Altered intercellular communication in lung fibroblast cultures from patients with idiopathic pulmonary fibrosis

Trovato‐Salinaro, Angela; Trovato-Salinaro, Elisa; Failla, Marco; Mastruzzo, Claudio; Tomaselli, Valerio; Gili, Elisa; Crimi, Nunzio; Condorelli, D. F.; Vancheri, Carlo

doi:10.1186/1465-9921-7-122

Cited by 54 publications

(38 citation statements)

References 42 publications

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“…We have shown that in primary lung fibroblasts from IPF patients there is a reduced expression of Cx43 and, by means of a dye-loading technique, we assessed gap junctional activity and showed a reduced intercellular communication in fibrotic fibroblasts compared with normal cells. The reduced cell-to-cell communication described in IPF fibroblasts is very similar to what has been described in cancer cells and may explain both the release from the restraint of contact-inhibition and uncontrolled proliferation that is present in these diseases [37]. The role of myofibroblasts in IPF and cancer Abnormal wound healing and exaggerated myofibroblast activation are not specific features of IPF; other conditions including fibromatosis, inflammatory myofibroblastic tumours and myofibroblastic cancers, such as myofibromas and myofibroblastomas, are also characterised by uncontrolled proliferation of myofibroblasts [38].…”

Section: Epigenetic and Genetic Abnormalities In Ipf And Cancersupporting

confidence: 54%

Common pathways in idiopathic pulmonary fibrosis and cancer

Vancheri¹

2013

Eur Respir Rev

149

105

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Idiopathic pulmonary fibrosis (IPF) is marked by a very disappointing survival rate and still represents a clinical dilemma. According to the current pathogenic hypothesis, chronic damage of the alveolar epithelium is followed by abnormal tissue repair and impairment of the alveolar structure. This process is driven by pathogenic events very similar to cancer, including epigenetic and genetic changes, altered response to regulatory signals, abnormal expression of microRNAs and activation of specific signalling pathways. IPF also resembles cancer with regard to its poor response to medical treatment and prognosis, which is very often worse than many cancers. We have hypothesised that IPF might be assimilated to a neoproliferative disorder of the lung. Viewing IPF as a cancer-like disease may satisfy the need for a better understanding of the pathogenesis of IPF by exploiting the large amount of knowledge that cancer biology evokes. The recognition of common pathogenic pathways between the two diseases may stimulate new clinical trials with cancer drugs, different drug combinations and different lines of drugs, as already experimented in oncology. Moreover, the concept of IPF as a cancer-like disorder may improve the attention given to this dreadful disease on a public, political and healthcare level. @ERSpublications Considering idiopathic pulmonary fibrosis as a cancer-like disorder may improve its treatment and investigation.

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Section: Epigenetic and Genetic Abnormalities In Ipf And Cancersupporting

confidence: 54%

Common pathways in idiopathic pulmonary fibrosis and cancer

Vancheri¹

2013

Eur Respir Rev

149

105

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“…We have shown that in primary lung fibroblasts from IPF patients there is also a reduced expression of Cx43 that resulted in a reduced gap junctional intercellular communication in fibrotic fibroblasts compared to normal cells. The reduced cell-cell communication described in IPF fibroblasts is very similar to that which 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]. …”

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confidence: 57%

A progression-free end-point for idiopathic pulmonary fibrosis trials: lessons from cancer

Vancheri

Bois

2012

Eur Respir J

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Idiopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease that results in increasing morbidity. To date there is only one licensed therapy for this condition and other agents are needed for this attritional disease. Efforts to study other agents have been obstructed by an increasing division of opinion about the most clinically meaningful end-point of phase III clinical trials to demonstrate efficacy. Many clinicians believe that an agent that impedes progression of the disease is more than acceptable and will encourage the pharmaceutical industry to further develop their IPF programmes. We have been impressed by the behavioural and biological similarities of cancer and IPF, and wondered if lessons could be learned about clinical trial design from lung cancer studies. Here, we set out our arguments that the similarities with cancer justify comparing the magnitude of therapeutic effects in clinical trials in nonsmall cell lung cancer with those in successful trials in IPF. We demonstrate that efficacy is of a similar magnitude in the two chronic lung diseases. We recommend that the demonstration of similar magnitudes of progression-free disease effect in IPF, using appropriate indices, should be considered as clinically meaningful benefit in future phase III clinical trials of novel therapies.KEYWORDS: Clinical trials, fibroblast/myofibroblast, forced vital capacity, lung cancer, pulmonary fibrosis, pulmonary function tests I diopathic pulmonary fibrosis (IPF) is a progressive fibroproliferative disease characterised by an accumulation of myofibroblasts in the alveolar wall, aberrant matrix deposition and subsequent distortion of the normal lung architecture. The disease results in progressive morbidity, worsening quality of life and an increasing dependence on others for the most basic of functional needs. The current paradigm of the pathogenetic process that results in IPF is that the disease is initiated by recurrent injury to the alveolar epithelium and evolves into an aberrant fibroproliferative response which progresses [1]. The cause(s) of the repeated injury is unknown but is thought to be the product of one or more environmental triggers operating within an individual whose genotype makes them susceptible to the disease [2]. More recently, IPF has been assimilated to a neoproliferative disorder based on the evidence that a number of pathogenic features of IPF are shared with cancer biology [3]. Genetic and epigenetic changes, delayed apoptosis and altered response to regulatory signals by myofibroblasts, reduced cellular communications and abnormal activation of specific signalling pathways have been shown to be hallmarks common to IPF and cancer. Consistent with this, COOL et al. [4] reported that ''fibroblast foci'', the characteristic defining lesions in IPF, are interconnected, forming a three-dimensional reticulum that resembles the tissue infiltration typical of cancer. The absence of monoclonality noted within the fibroblast foci and their incapacity to metastasise ...

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“…Furthermore, in fibroblasts from keloid and hypertrophic scar tissue, compared with normal skin, CX43 levels are significantly lower. We have also shown that in primary lung fibroblasts from IPF patients there is a reduced expression of CX43 which functionally translates into a reduced gap junction intercellular communication (GJIC), an event linked with loss of contact inhibition restraints and as such with uncontrolled proliferation [45].…”

Section: Altered Cell-cell Communicationsmentioning

confidence: 96%

Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology

Vancheri¹,

Failla²,

Crimi³

et al. 2010

Eur Respir J

417

329

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Several clinical trials have recently targeted specific pathways implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF). However, IPF remains plagued by a median survival of 3 yrs and emphasises the need for further research with new insights and perspectives. The prevailing pathogenic hypotheses assume that either an inflammatory process or an independent epithelial/fibroblastic disorder may propagate the disease process. Based on knowledge developed with considerable scientific evidence, we provide our perspectives with an alternative point of view that IPF be considered as a neoproliferative disorder of the lung. Genetic alterations, response to growth and inhibitory signals, resistance to apoptosis, myofibroblast origin and behaviour, altered cellular communications, and intracellular signalling pathways are all fundamental pathogenic hallmarks of both IPF and cancer. The concept of IPF as a lethal malignant disorder of the lung might extend beyond the pathogenic link between these two diseases and disclose new pathogenic mechanisms leading to novel therapeutic options, adopted from cancer biology. Moreover, this vision might dawn the awareness of the public, political and scientific community of this devastating disease from an angle different from the current perception and provoke new ideas and studies to get a better understanding to control the otherwise relentless progressive disease.

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Altered intercellular communication in lung fibroblast cultures from patients with idiopathic pulmonary fibrosis

Cited by 54 publications

References 42 publications

Common pathways in idiopathic pulmonary fibrosis and cancer

Common pathways in idiopathic pulmonary fibrosis and cancer

A progression-free end-point for idiopathic pulmonary fibrosis trials: lessons from cancer

Idiopathic pulmonary fibrosis: a disease with similarities and links to cancer biology

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