Sanford H. Barsky M.D.

Lay Description

Bronchioalveolar lung carcinoma (BAC) is a form of lung cancer for which etiology and pathogenesis are controversial. While squamous cell carcinomas and small cell carcinomas have shown an overall decrease in incidence during the past four decades, BACs and peripheral adenocarcinomas (PAC) have shown exponential increases during this same time period. Some of the distinguishing pathological, biological, epidemiological, and perhaps etiological features of BAC/PAC include its peripheral location, its association with desmoplasia (scarring), its comparatively high female/male ratio, and its high incidence of multifocality. These days there is emerging evidence that stem cells and transformed stem cells are the source and reservoir of many human cancers. Based on the multifocality of BAC/PAC, its penchant for recurring, its penchant for initially responding to targeted therapies and then relapsing and other unique biological features, certainly the applicability of the stem cell hypothesis to human BAC/PAC would appear real and worthy of study. We recently made a startling observation in patients who had received a bone marrow transplant from a different sex donor for non-Hodgkin’s lymphoma or leukemia who years later developed lung BAC/PAC. The BAC/PAC which developed was of donor origin! This could only have been the case if a stem cell derived from the bone marrow of the donor was the cell of origin of the BAC/PAC. We would like to test this hypothesis further in two experimental preclinical models, so-called transgenics which express certain genes that cause the model to develop BAC/PAC. If our hypothesis is correct and, in fact, a bone marrow-derived stem cell gives rise to BAC/PAC then transplanting the bone marrow from these transgenic models into normal recipients (which do not normally get lung cancer) will result in the recipient models getting BAC/PAC. Conversely transplanting bone marrow from normal donors into the transgenic models whose original bone marrow we destroy by irradiation should result in a decrease or absence of BAC/PAC. If we can demonstrate experimental proof for our hypothesis, we should be able to identify and purify the putative bone marrow stem cell that gives rise to BAC/PAC because they will be marked with the causative transgene.

Scientific Abstract

Bronchioalveolar lung carcinoma (BAC) is a form of lung cancer for which etiology and pathogenesis are controversial. While squamous cell carcinomas and small cell carcinomas have shown an overall decrease in incidence during the past four decades, BACs and peripheral adenocarcinomas (PAC) have shown exponential increases during this same time period. Some of the distinguishing pathological, biological, epidemiological, and perhaps etiological features of BAC/PAC include its peripheral location, its association with desmoplasia (scarring), its comparatively high female/male ratio, and its high incidence of multifocality. These days there is emerging evidence that stem cells and transformed stem cells are the source and reservoir of many human cancers. Based on the multifocality of BAC/PAC, its penchant for recurring, its penchant for initially responding to targeted therapies and then relapsing and other unique biological features, certainly the applicability of the stem cell hypothesis to human BAC/PAC would appear real and worthy of study. We recently made a startling observation in patients who had received a bone marrow transplant from a different sex donor for non-Hodgkin’s lymphoma or leukemia who years later developed lung BAC/PAC. The BAC/PAC which developed was of donor origin! This could only have been the case if a stem cell derived from the bone marrow of the donor was the cell of origin of the BAC/PAC. We would like to test this hypothesis further in two different transgenic preclinical models that spontaneously develop lung BAC/PAC. We propose using a transgenic preclinical model where a mutant form of p53 (p53-273H) is placed under the transcriptional control of the lung-specific human surfactant protein C (SP-C) promoter. In this transgenic model lung BAC/PAC develop in nearly 100% of mice in 4-6 months. We propose also using a second but different transgenic preclinical model where the SV40 large T antigen is expressed under control of the mouse Clara cell Mr 10,000 protein promoter (CCSP). These models develop BAC/PAC in 4-8 months. We propose to test our hypothesis by first transplanting bone marrow from the transgenic models into lethally irradiated wild type models. Secondly we plan to transplant bone marrow from wild type models into lethally irradiated transgenics. Models exhibiting successful engraftment will be monitored for the development of lung BAC/PAC. If our hypothesis is correct, that lung BAC/PAC, in fact, develop from bone marrow-derived stem cells, then we will observe an increase in BAC/PAC in the wild type recipients receiving the transgenic marrows and a decrease in BAC/PAC in the transgenic recipients receiving the wild type marrows. If we can demonstrate proof for our hypothesis, we should be able to identify and purify the putative bone marrow stem cell that gives rise to BAC /PAC because they will be labeled with the causative transgene.