Research Highlights
The Cancer Stem Cell Program builds on the momentum of past breakthroughs at Stanford in stem cell research and therapy. This includes the first isolation of pure blood-forming stem cells in mice in 1984 and in humans in 1991. These discoveries by Irv Weissman, MD, laid the foundation for the first clinical trials in which patients received cancer-free stem cells to regenerate bone marrow function following aggressive chemotherapy.
Today program members are leading the discovery of new tissue-specific and cancer stem cells as well groundbreaking investigations into commonalities between stem cell and cancer biology. Their work is yielding exciting possibilities for new diagnostic, treatment and prevention strategies across all cancer types.
The major accomplishments of program members are summarized below:
- Discovery, in 1982, of the first member of the Wnt gene family, Wnt1, as an oncogene in mouse mammary tumors was made by Dr. Nusse (working with Dr. Harold Varmus). Using the Mouse Mammary Tumor Virus (MMTV) for proviral tagging, Dr. Nusse cloned Wnt1 (called int1 at the time) as an integration site and found the Wnt1 gene to be transcriptionally activated. This work demonstrated how MMTV causes breast cancer, uncovered the existence of Wnt genes and led numerous other investigators to using proviral tagging for the discovery of oncogenes.. Many tumors induced by the mouse mammary tumor virus contain a provirus integrated in the same region of the host genome. (Cell 31; 99-109,1982)
- Members of the program have made several subsequent major discoveries in the area of Wnt signaling, including the identification of wingless in Drosophila as the homolog of Wnt1 (Cell 50; 649-657,1987) . This seminal finding opened the field to the use of fly genetics to understand Wnt signaling mechanisms in cancer.
- Following genetic and other approaches, Dr. Nusse's group showed that beta-catenin plays a key role in Wingless signaling (Development 116; 711-9,1992) . This work implicated beta-catenin firmly into the Wnt pathway and suggested that it could act in tumorigenesis as well.
- Together with Dr. Jeremy Nathans' group, a member of the program identified the Frizzled molecules as receptors for Wingless and other Wnts. (Nature 382; 225-30,1996) .
- The first successful purification of active Wnt proteins, showing that they are lipid-modified and act as stem cell growth factors was done by Dr. Nusse's laboratory. This work provides one of the links between stem cell proliferation and cancer cells. (Nature 423; 448-52,2003)
- Members of the program were one of the first to generate monoclonal antibodies to c-erbB2/neu, and established that the gene was overexpressed in a specific subset of human breast cancers (N Engl J Med 319; 1239-45,1988) .
- Dr. Clarke's laboratory was the first to identify cancer stem cells in a solid tumor, breast cancer (Proc Natl Acad Sci U S A 100; 3983-8,2003) . His laboratory has subsequently identified cancer stem cells in other solid tumors. These findings can be exploited to improve the outcome of patients with cancers of epithelial origin, the major cause of cancer-related mortality.
- Members of the program have the first to identify a self-renewal pathway in adult normal stem cells (Nature 423; 302-5,2003) . Identification of these pathways has major implications in normal and malignant stem cell biology. Differences between normal stem cells and cancer stem cells may provide novel therapeutic targets. Inhibition of self-renewal in cancer stem cells but not normal stem cells could result in more effective treatments.
- Dr. Clarke's laboratory was the first to show that expansion of normal stem cells is regulated by multiple genes (J Immunol 168; 635-42,2002) ;. This study laid the groundwork for the identification of self-renewal genes in adult stem cells and for the identification of solid tumor stem cells.
- Dr. Clarke's laboratory was the first to identity a cancer stem cell gene signature. This signature can be used to predict survival of patients with multiple types of solid tumors including prostate cancer. This observation will form the foundation of a clinical study to try to improve therapy of prostate cancer.
- Dr. Weissman' group was the first to isolate both mouse and human hematopoietic stem cells (HSCs) (Science 241; 58-62,1988;Immunity 1; 661-73,1994;J Exp Med 175; 175-84,1992) . The methods used to identify HSCs are the foundation of modern adult stem cell biology.
- Members of the program have identified key downstream developmental intermediates of HSCs (Cell 91; 661-72,1997;Nature 404; 193-7,2000) . This has permitted the laboratory to precisely identify the cell of origin of certain types of leukemia (N Engl J Med 351; 657-67,2004;Cell 119; 431-43,2004) .
- Dr. Weissman's laboratory was the first to use SCID mice to make mouse/human xenografts (Science 241; 1632-9,1988) . This has enabled the identification of multiple types of normal and malignant human stem cells (Proc Natl Acad Sci U S A 97; 14720-5,2000) .
- Dr. Weissman's laboratory was the first to isolate the leukemia stem cells (LSC) in patients with Chronic Myeloid Leukemia (CML) in blast crisis . This will allow us to devise strategies to better diagnose and treat this disease.
- Members of the Program were the first to show in aml1/eto AML that the HSC compartment did not contain LSC, but up to 40% of HSC had the aml1/eto translocation as a preleukemic step, yet made normal blood cells. The LSC were in a CD90- population of multipotents (Proc Natl Acad Sci U S A 97; 7521-6,2000)
- Members of the Program discovered and cloned the genes used for lymphocyte homing from the bloodstream, and demonstrated their role in the invasion and target organ homing of mouse melanomas and insulinomas. Dr. Weissman's laboratory also showed that normal HSC leave the marrow and circulate through the blood to enter distant marrow niches at a high rate, and defined the homing and chemokine receptors used in such homing. This study provides the basis of myelogenous leukemia distribution throughout the marrow (Cell 44; 673-80,1986;Proc Natl Acad Sci U S A 98; 3976-81,2001;Cell 77; 335-47,1994;Science 294; 1933-6,2001) .
- Members of the Program were the first to isolate prospectively from cancer patients mobilized blood HSC free from all other cells, including cancer cells (from NHL from indolent lymphomas, and multiple myeloma). These cancer-free HSC were used in autologous hematopoietic regeneration of these patients following myeloablative combination chemotherapy. The breast cancer trial was conducted by Dr. Robert Negrin in Program 8 (Hematopoietic Cell Transplantation and Immune Reconstitution) (Biol Blood Marrow Transplant 6; 262-71,2000) .
- Dr. Fuller's laboratory has identified key interactions between Drosophila male germ (sperm stem) cells and the stromal cells that support them (Science 294; 2542-5,2001;Nature 407; 750-4,2000) . This system demonstrates the importance of interactions with the niche in governing stem cell behavior.
- Dr. Fuller's laboratory was the first to show that the Cadherin/Wnt adhesion pathway regulates polar cell division of Drosophila germ cells (Science 301; 1547-50,2003) . This pathway has subsequently been shown to regulate polar cell division in mammalian epithelial stem cells and may play a role in the progression of tumors of epithelial origin.
- Dr. Scott's laboratory was the first to identify the role of sonic hedgehog (SHH) in basal cell carcinoma and in mouse meduloblastoma (Science 276; 817-21,1997) . SHH is thought to play a key role in the self-renewal of certain types of stem cells. Recent evidence implicates this pathway in prostate cancer.
- Dr. Scott's laboratory identified the Granular Neural Precursor (GNP) as the cell of origin of medulloblastoma and discovered that defects in the SHH pathway cause medulloblastoma in humans (Neuron 22; 103-14,1999;Immunity 19; 169-82,2003) .
- The cells and molecules responsible for resistance to engraftment of purified allogeneic HSCs have been identified. Dr. Shizuru and others have shown that cells with NK determinants constitute a significant barrier to allogeneic HSC engraftment, and that transplanted whole BM contains a population of cells that facilitates engraftment (Ann Rev Med 56:509, 2005).
- Identification of the cells and molecules that confer graft vs. leukemia/lymphoma (GVL) effects in a model of B cell lymphoma relapse after HSC transplant. Dr. Shizuru's studies show that while purified allogeneic HSCs have no GVL activity, a population of BM cells that express CD3 and CD8 which can be expanded ex vivo result in control of disease without significant GVHD (Blood 97:2923, 2001; Biol Blood Marrow Transpl 7:532, 2001).
- The first known protein mediator of mitochondrial fusion, required for formation of specialized mitochondrial structures in spermatids was identified in Dr. Fuller's laboratory (Cell 90; 121-9,1997) .
- The NF-AT signaling pathway in lymphocytes was discovered by Dr. Crabtree This pathway involves a famly of NF-ATc transcription factors, calcineurin and Ca2+and is also important for development of the mammalian heart and the functioning of specific neurons in the hippocampus (Science 241; 202-5,1988;Nature 357; 695-7.,1992) .
- Dr. Crabtree's laboratory has purified ATP dependent chromatin remodeling complexes from populations enriched in stem cells and found that the subunit composition of these complexes changes as they progress from progenitors to differentiated cells. Further, mice generated with conditional deletions of the Brg ATPase subunit revealed that it is essential for stem cell renewal in the nervous system and for neurogenic divisions; (Immunity 19; 169-82,2003) . They also found that 3-fold overexpression of a neural stem cell specific subunit is sufficient to direct self renewal in transgenic mice.
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