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Rapid advances in murine lung cancer modeling provide continuous challenges for pathologists. The issue of murine lung tumor classification was addressed at the MMHCC workshop on mouse models of lung cancer held in Boston on June 20-22, 2001. A panel of human, veterinary and experimental pathologists devised a new system for the classification of murine lung tumors specifically designed to accommodate appearances of novel nosological units, and to provide guidelines for the comparison of human and mouse lesions. These guidelines have been recently published; see references 121, 122.

1. Epithelial

1.1 Hyperplasia

1.1.1 Epithelial

1.1.2 Neuroendocrine

1.2 Tumors

1.2.1 Benign

1.2.1.1 Papilloma

1.2.1.2 Adenoma

1.2.1.2.1 Papillary

1.2.1.2.2 Solid

1.2.1.2.3 Adenoma with mixed subtypes

1.2.2 Preinvasive Lesions

1.2.2.1 Squamous dysplasia

1.2.2.2 Atypical adenomatous hyperplasia

1.2.3 Malignant

1.2.3.1 Squamous cell carcinoma

1.2.3.2 Adenocarcinoma

1.2.3.2.1 Papillary

1.2.3.2.2 Acinar

1.2.3.2.3 Solid

1.2.3.2.4 Mixed Subtypes

1.2.3.2.5 NOS

1.2.3.3 Adenosquamous carcinoma

1.2.3.4 Neuroendocrine carcinoma

1.2.3.5 Carcinoma, other

2. Soft Tissue
3. Mesothelial
4. Miscellaneous
5. Lymphoproliferative
6. Secondary
7. Unclassified
8. Tumor-Like

The lung tumors in existing murine models are typically less aggressive than human tumors, with weaker stromal reaction and fewer metastasis. Thus the differential diagnosis between benign, pre-malignant and malignant tumors is more difficult to make in mice, and a consensus for such diagnosis has not yet been reached. The differential diagnosis of adenocarcinoma is based on the presence of large pleomorphic cells with vesicular nuclei, prominent nucleoli, undifferentiated cytoplasm and frequent mitoses.

The cell of origin of murine pulmonary adenocarcinoma is still debatable, but may prove to be a useful criterion for tumor classification. It remains unclear whether tumors can arise from alveolar type II cells, Clara cells and multipotent stem cells or only from one or a subset of these cell types (1, 34, 38, 52, 58, 70, 72, 92, 93, 104). Immunohistochemical staining is often employed as a means to determine the cell of origin of individual tumors (see protocols). Staining with anti-SP-C antibodies is performed to identify cells of the alveolar type II cell lineage, whereas anti-CC10 antibodies are used to determine Clara cell lineage (see staining protocols). Historically, SP-A has been used as a marker for type II cells, but it is also expressed by Clara cells, although at lower levels, and thus is not as specific a marker as SP-C. Of note, there is evidence to suggest that tumor cells may have the potential to transdifferentiate or may downregulate expression of CC10 and upregulate expression of SP-A as they progress (39, 48, 105) . Therefore, the reactivity of the tumor may not always accurately reflect the cell of origin of the tumor, however it is useful in assessing the differentiation state of the tumor itself. Enzyme histochemistry is also employed as a means to determine the cell of origin. Clara cells exhibit high levels of both glyceraldehyde-3-phosphate dehydrogenase (G3PD) and succinate dehydrogenase activity whereas alveolar type II cells show only slight activity. Histochemical staining has demonstrated that the enzyme activity of solid adenomas is similar to that of alveolar type II cells, whereas the enzyme activity of papillary adenomas is more like that of Clara cells (34, 92).

Pre-clinical Therapeutics
Pre-clinical testing of lung cancer therapeutics has been largely carried out using xenograft models in which human lung cancer cell lines have been subcutaneously injected into immunodeficient mouse strains. However, xenograft models may not accurately mimic the behavior of lung tumors arising in the cellular microenvironment of the normal lung. Accordingly, xenograft models have a poor record of accurately predicting the clinical efficacy of anticancer agents. Carcinogen induced and genetically modified murine lung cancer models that have been shown to accurately mimic the human disease may provide more predictive models in which to perform pre-clinical testing.

As discussed above, strain A mice are highly susceptible to the development of pulmonary adenocarcinoma after treatment with a variety of chemical carcinogens. Studies testing the efficacy of chemo-intervention with cis-platinum alone or in combination with indomethacin, metoclopramide or nifedipine demonstrated the usefulness of this model system for evaluating therapeutics (2). The strain A model has also been used to assess the ability of potential chemopreventive agents to protect against the development of carcinogen induced lung tumors (33, 107). Furthermore, studies have been conducted to test the efficacy of both chemotherapeutics and chemopreventives for treating or preventing carcinogen induced lung tumors in F1 mice resulting from the cross of strain A mice to p53 null or transgenic p53 mice (112). This study demonstrates the usefulness of transgenic models for pre-clinical testing. Further examination of existing models, both genetically modified and carcinogen induced, with conventional drugs will provide additional support for their predictive value.

The limited success of lung cancer treatment with classic chemotherapeutic agents has led researchers to focus on the development of targeted therapeutics aimed at the molecular mechanisms underlying lung tumorigenesis. Genetically modified mouse models may prove to be extremely well suited for pre-clinical testing of compounds aimed at inhibiting the particular genetic alterations driving tumor formation in a given model. Genetically modified murine cancer models have been used to examine the efficacy of some targeted therapeutics. For example, farnesyl transferase inhibitors that act to inhibit Ras signaling have been tested in several models whose genetic modifications result in upregulation of ras signaling. These studies demonstrated that FTIs are effective for treating some, but not all tumor types (115). These findings illustrate the importance of testing novel lung cancer therapeutics in well defined lung cancer models.

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