Comparative Pathobiology of Environmentally Induced Lung Cancers in Humans and Rodents

Abstract

Lung cancer is the number one cause of cancer-related deaths in humans worldwide. Environmental factors play an important role in the epidemiology of these cancers. Rodents are the most common experimental model to study human lung cancers and are frequently used in bioassays to identify environmental exposure hazards associated with lung cancer. Lung tumors in rodents are common, particularly in certain strains of mice. Rodent lung tumors are predominantly bronchioloalveolar carcinomas and usually follow a progressive continuum of hyperplasia to adenoma to carcinoma. Human lung cancers are phenotypically more diverse and broadly constitute 2 types: small cell lung cancers or non-small cell lung cancers. Rodent lung tumors resulting from exposure to environmental agents are comparable to certain adenocarcinomas that are a subset of human non-small cell lung cancers. Human pulmonary carcinomas differ from rodent lung tumors by exhibiting greater morphologic heterogeneity (encompassing squamous cell, neuroendocrine, mucinous, sarcomatoid, and multiple cell combinations), higher metastatic rate, higher stromal response, aggressive clinical behavior, and lack of a clear continuum of proliferative lesions. In spite of these differences, rodent lung tumors recapitulate several fundamental aspects of human lung tumor biology at the morphologic and molecular level especially in lung cancers resulting from exposure to environmental carcinogens.

Evaluating the mechanistic evidence and key data gaps in assessing the potential carcinogenicity of carbon nanotubes and nanofibers in humans

“…The finding of significantly increased focal adenomatous alveolar hyperplastic lesions in mice (male, B6C3F1) following inhalation of MWCNT-7 (Sargent et al 2014) provides evidence of pre-neoplastic changes similar to those observed in humans that have the potential to progress to bronchiolo-alveolar carcinoma or adenocarcinoma (Brambilla et al 2001; Pandiri 2015). Presently, the mechanism of the cell proliferation is not known.…”

“…Such studies are needed to improve the mechanistic evidence for assessing the potential carcinogenicity of CNT and CNF, since it is not feasible to perform chronic rodent bioassays of each material. The focal adenomatous hyperplasia observed in alveolar epithelial tissues in mice exposed to MWCNT-7 (Sargent et al 2014) is considered to resemble the preneoplastic lesion AAH in humans (Section “Epithelial cell proliferation and hyperplasia—MWCNT”) (Brambilla et al 2001; Pandiri 2015). It would be useful to investigate any influence of the physico-chemical properties of the material on the dose–response relationships for pre-neoplastic lesions.…”

“…It would be useful to investigate any influence of the physico-chemical properties of the material on the dose–response relationships for pre-neoplastic lesions. It would also be useful to further examine the characteristics of the hyperplastic lesions in animals with the characteristics of preneoplastic lesions (e.g., AAH) in humans (Section “Epithelial cell proliferation and hyperplasia—MWCNT”) (Brambilla et al 2001, Pandiri 2015). …”

“…Focal adenomatous alveolar epithelial hyperplasia was observed at 17 months post-exposure in the terminal bronchiole/alveolar duct region (Sargent et al 2014). In humans, atypical adenomatous hyperplasia (AAH) is the form of primary bronchoalveolar hyperplasia considered to be preneoplastic (Foley et al 1991; Malkinson 1991; Brambilla et al 2001; Ress et al 2003; Sargent et al 2014; Pandiri 2015). For this reason, Sargent et al (2014) separated hyperplasia into general hyperplasia and focal adenomatous hyperplasia, which resembles human AAH and which was “characterized by an increase in the number of crowded alveolar epithelial cells that outlined contiguous alveolar septa in discrete, generally random locations” (Sargent et al 2014).…”

Kras, Egfr, and Tp53 Mutations in B6C3F1/N Mouse and F344/NTac Rat Alveolar/Bronchiolar Carcinomas Resulting from Chronic Inhalation Exposure to Cobalt Metal

“…Alveolar/bronchiolar adenomas/carcinomas that arise either spontaneously or from chronic chemical exposure are morphologically similar to the adenocarcinoma subtype of the non-small cell lung cancer (NSCLC) in humans (Hong et al , 2008, Pandiri, 2015, Tuveson and Jacks, 1999). Spontaneous lung (SL) tumor (alveolar/bronchiolar carcinomas) incidence in the B6C3F1/N mouse strain ranges from 9.5% (female) – 27.7% (male) (all routes, all vehicles, NTP historical control database 2013), and the incidence of lung tumors after exposure to certain chemicals was considerably higher in chronic NTP bioassays (NTP, 2013a).…”