Stem Cells in Breast Cancer Metastasis
Creators: name: University Of California Office Of The President
Publisher: name: University of California Office of the President
publisherIdentifier: https://ror.org/00dmfq477
publisherIdentifierScheme: ROR
Year: 2024

description: The concept of a reservoir of stem cells, persisting throughout life and capable of multi-lineage differentiation is firmly established and well characterized for blood cells (i.e., RBCs, WBCs &amp; platelets). Less well understood, but compelling in its rationale, is the idea that most normal human tissues are maintained through the differentiation of a resident population of slowly cycling stem cells. These tissue specific stem cells regenerate themselves and produce more differentiated progeny, to yield the complex array of cell types that define most bodily organs. In the mammary gland, cyclical changes of estrus and pregnancy, repeated though a lifetime, require the balanced maintenance of a diversity of cell types in response to a variety of external hormonal stimuli. This renders the mammary gland susceptible to the introduction of genetic errors that may accumulate in its stem cell population and ultimately lead to malignancy and metastasis. Recent studies have identified a small fraction of primary tumor cells with early progenitor phenotypes and genetic fingerprints as the tumor initiators. A key property of stem cells is their extreme migratory responsiveness to cytokinetic and hormonal signals. We therefore propose that a population of aberrant stem-like cells within a breast tumor is critically involved in the initiation of metastatic disease.
 
 
 
 
 
 
 
 The CBCRP-supported collaboration involves expertise in the biology of breast cancer metastasis (Drs. Felding-Habermann and O'Sullivan), expertise in proteomic analysis (Dr. Yates), and expertise in stem cells in neuron biology (Dr. Snyder). Our background from these three disciplines will be integrated into the project aims. Our central hypothesis is that metastatic breast cancers arise when mutated cells with the capacity for self-renewal and in situ differentiation arrive at distant organs and, in response to signals from their new environment, differentiate along pathways which allow them to adapt to and ultimately thrive in the new environment. We will expand upon data implicating epithelial stem cell-like tumor initiator populations as the source of human solid tumors to show that these progenitor cells are also responsible for metastatic disease. First, we aim to isolate and characterize progenitor cell populations from normal breast tissue, breast tumors and metastases. In this aim, we will fully work out the parameters by which we can identify tumor progenitor cells from patient samples and human breast cancer cell models. Because no single method has yet been universally adopted to identify epithelial stem/progenitor cells, we plan to use dye exclusion, cell surface markers, bromodeoxyuridine incorporation, cytoskelton staining, and tumorigenicity experiments as our initial approaches to defining and isolating progenitor populations.
 
 
 
 
 
 
 
 Our second aim is to analyze whether progenitor cell populations from human breast tumors give rise to distant metastases. In this aim, we will take the isolated progenitor populations and test their ability to colonize target organs of breast cancer metastasis in immune deficient mice both from the circulation and from primary tumors established in the mammary fat pads. We will use cell labeling, quantitative PCR and immuno histochemistry to identify and quantify tumors and metastases.
 
 In our third aim, we will explore the possibility of harnessing normal stem cells for guided targeting of distant metastases, particularly those that develop in the brain. One of us (Snyder) found that neural stem cells have a stunning tropism to diseased areas in the brain. We will establish brain metastases in immune deficient mice by introducing human breast cancer cells that home to the brain as a target organ, and then test whether normal neural stem cells seek out areas of tumor growth. Genetically tagged with distinct variants of luciferase, tumor cells and neural stem cells can be detected and distinguished by non-invasive imaging. This will allow us to follow both cell types during disease progression in individual animals, and to test the concept that neural stem cells may potentially serve to deliver anti-tumor gene products or pro-drugs and eventually help to repair the tumor-afflicted brain.
 
 
 
 
 
 
 
 In our final aim, we will analyze protein profiles of stem cells from normal breast tissue, breast tumors and metastases. We will establish protein expression "signatures" of matched samples from the same patient using multidimensional proteomic (MudPIT) analysis, and compare progenitor cells with differentiated cell populations from each tissue type. With this approach, we hope to reveal a comprehensive spectrum of differences between the progenitor cells and their progeny and the influence of the site of metastasis on gene and protein expression.
 
 
 
 
 
 
 
 Understanding the biology of the tumor-initiating cell population in breast cancer would have a profound impact on how we design therapies, particularly those targeting metastatic disease in the brain. It would also greatly enhance our ability to predict the metastatic potential of individual tumors and help patients and their physicians to select their most promising treatment options.