Carla F. Kim Ph.D.

Recipient of the LUNGevity Foundation/Joan’s Legacy Research Grant. Funded equally by Joan's Legacy and the LUNGevity Foundation.

Lay Description

Lung cancer is the leading cause of death from cancer worldwide. In the United States alone, 160,000 people are expected to die from lung cancer in 2007. These high lung cancer mortality rates are attributed to the fact that most patients are not diagnosed until they have advanced disease, for which there are few or no therapeutic options. As such, it is imperative to improve our very limited understanding of the nature of lung cancer cells in order to develop more effective therapies.

It has been known for many years that only a small fraction of the cells within a tumor are needed for tumor growth. These cells are now recognized as “cancer stem cells” because they, like the stem cells in normal tissues, are able to renew themselves. Although cancer stem cells represent only a small proportion of the tumor, they are believed to be more resistant to chemotherapy than the rest of the cells within a tumor. Therefore, in order to effectively treat cancer, it may be crucial to identify cancer stem cells and then develop therapies that specifically eliminate these key cells.

In the proposed studies we will focus on the specific goal of identification of cancer stem cells in bronchioalveolar carcinoma (BAC), a type of lung cancer that is particularly resistant to traditional therapeutic methods, and, therefore likely to contain cancer stem cells. Interestingly, BAC arises in the same part of the lung where I first identified stem cells in the model lung. Therefore, there may be similarities between the model lung stem cells we discovered and BAC stem cells, making our group uniquely positioned to study BAC. We have recently created a new test for lung cancer stem cells by transplanting subsets of tumor cells into recipient models and comparing the ability of these subsets to give rise to new tumor growth. We will use this system to identify BAC stem cells and understand the properties that distinguish them from other tumor cells. Defining the methods to isolate BAC stem cells is a prerequisite to developing therapeutic strategies to eliminate the cells that allow BAC to grow. Our work will provide the first step towards identifying new ways to study and treat BAC.

Scientific Abstract

We previously discovered a population of stem cells named BronchioAlveolar Stem Cells (BASCs) in the model lung. BASCs reside in the bronchioalveolar junction and appear to be important for maintaining bronchiolar and alveolar cells during normal lung homeostasis. Using a preclinical model that mimics the most common form of lung cancer in humans, we determined that BASCs may be the cells-of-origin of lung adenocarcinoma. Recent work in other solid tumors indicates that stem cells may also be important in the continued growth of tumors; in breast, colon, and brain cancers, only a small fraction of the cells are required for tumor growth in transplantation assays. These rare cancer cells have been named “cancer stem cells,” and it is hypothesized that they are resistant to chemotherapeutic agents. In order to cure cancer, it may be crucial to develop treatments that specifically eliminate cancer stem cells. However, it is not known if cancer stem cells play a role in lung cancers.

Bronchioalveolar carcinoma (BAC) is a subtype of lung cancer that is usually resistant to traditional chemotherapeutic strategies, raising the possibility that BACs contain a population of cancer stem cells. BAC arises in the terminal bronchioalveolar regions and usually exhibits features of bronchiolar and/or alveolar cells. Given that human BAC occurs in same anatomical location where we identified BASCs in murine lung, there are likely to be similarities between BASC and BAC biology. Therefore, our prior discovery of BASCs makes our group uniquely positioned to develop new strategies to study BAC.

We hypothesize that bronchioalveolar carcinomas (BAC) are maintained by a cancer stem cell population. The Specific Aims of our research are (1) To identify BAC stem cells using murine transplantation assays and (2) To use stem cell culture methods to identify chemicals that inhibit BAC stem cells. First, we will compare the ability of isolated human BAC cell populations to propagate lung cancer in immunocompromised mice. We will use currently defined BASC markers and markers of cancer stem cells from other tissues to identify a cancer stem cell population in BAC. In parallel studies, we will use our BASC culture system to propagate BAC cells and perform a screen to identify small molecules that inhibit stem cell properties of BAC cells.

Understanding how to distinguish lung cancer stem cells from other tumor cells will highlight new ways to study and treat BAC. If drugs can be developed to inhibit the growth of the cancer stem cells we identify, they may be the most promising form of therapy for BAC patients. The unique features of BAC stem cells may also be useful as indicators of tumor severity or for imaging tumor growth in patients.