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Expression of IL-32 in Human Lung Cancer Is Related to the Histotype and Metastatic Phenotype

¹ Department of Oncology and Neurosciences, Anatomic Pathology Section, "G. d'Annunzio" University; and ² Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy

Correspondence and requests for reprints should be addressed to Dr. Emma Di Carlo, M.D., Ph.D., Anatomia Patologica, Ospedale Clinicizzato "SS Annunziata," Via dei Vestini, 66100 Chieti, Italy. E-mail: edicarlo{at}unich.it

Rationale: A strong link has been recently demonstrated between inflammation and lung cancer. Thus, we investigated whether the proinflammatory cytokine IL-32 may be involved in lung carcinogenesis and hence provide a novel therapeutic target.

Objectives: Lung cancer subtypes display different clinical outcomes. We have set out to clarify the role of IL-32 in the physiopathology of the main histotypes.

Methods: IL-32 expression, as visualized by immunohistochemistry on 23 premalignant and 148 malignant lesions, was correlated with clinicopathological and survival data. Confocal microscopy, microdissection, and real-time reverse transcription–polymerase chain reaction were used to identify cell sources and expression levels of IL-32.

Measurements and Main Results: IL-32 expression was lacking in the majority of squamous-cell carcinomas (SCC) (76%) and their precursor lesions, but strongly up-regulated in most adenocarcinomas (AC) (73%) and their precursors, 64% of large-cell carcinomas, and 77% of small-cell lung cancers. Lymph node metastases frequently developed from IL-32–expressing lung cancers, and especially (82%) from those endowed with an IL-32–expressing leukocyte infiltrate (TIL) mainly composed of CD68⁺ macrophages, CD4⁺ T lymphocytes, and DC-SIGN⁺ dendritic cells. Expression levels of IL-32 by both TIL and tumor cells (TC), particularly in AC and SCC, were paralleled by those of IL-6, IL-8, and vascular endothelial growth factor in the same cell population and correlated with high intratumor microvessel density and poor clinical outcome.

Conclusions: IL-32 is probably implicated in the pathogenesis of most lung cancer histotypes but unlikely in that of SCC. Its TIL and TC expression are both associated with acquisition of an invasive and metastatic phenotype and may be a useful prognostic indicator.

Key Words: lung cancer • cytokines • tumor microenvironment • inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Lung cancer consists of distinct tumor histotypes characterized by different biological behavior and clinical outcomes. Because inflammation plays a key role in lung carcinogenesis, investigation of the role of the recently identified proinflammatory cytokine IL-32 in this process, with respect to individual histotypes, may lead to the detection of new therapeutic targets. What This Study Adds to the Field IL-32 was differentially expressed by lung cancer histotypes. It was lacking on most squamous cell carcinomas (SCC) and their precursor lesions. By contrast, its strong expression by most adenocarcinomas (AC) and their precursors, as well as most large-cell carcinomas and small-cell lung cancers, points to its involvement in their pathogenesis.

 

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