1. The Microenvironment, Stem Cells, and Cancer

2. Microenvironment Signaling molecules – G-CSF – Erythropoietin Cell-cell contact – Adherens junctions – Gap Junctions – Desmosomes Extracellular matrix – Collagen – Fibronectin – Laminin Forces – Elasticity – Compression – Stiffness

3. Niche: Stem cell behavior control Adult stem cells such as intestinal crypt stem cells are tightly regulated by the environment around them – View: Intestinal Crypt Stem Cells - A Clonal Conveyor BeltIntestinal Crypt Stem Cells - A Clonal Conveyor Belt – Sometimes mutations cause bad behaviors Stem cells have the property to divide asymmetrically – One daughter cell stays a stem cell – The other daughter cell changes, or differentiates

4. Blood cell differentiation Granulocyte Colony Stimulating Factor Erythropoietin Push common myeloid progenitor cell to become red blood cells or white blood cells (leukocytes) G-CSF and Epo are signaling molecules that initiate signaling pathways that lead to gene expression and phenotype change – Transcription and translation

5. Cell interactions Tight junctions – Form a fluid and ion impermeable sheet – Allows for different functions on different sides of the sheet Anchoring junctions – Two types: adherens and desmosomes Built from cadherins (outside) and catenins (inside) – Adherens: attach to actin cytoskeleton – Desmosome (strong): attach to keratin filaments Gap junctions – Channels between cells

6. The Matrix Like a stem cell’s dorm room Concrete, rebar, wood posts, furniture Cells reside within this non-living world In the body the extracellular matrix gives tissues their structural and mechanical properties The components of the matrix contribute to tissue specificity of cells

7. Forces Elasticity: what is the stiffness of a tissue? – Brain < skin < muscle < bone Cells can sense the tissue stiffness They can also respond to the stiffness by changing shape and gene expression Mesenchymal stem cells grown on gels – Stiffness brain = neurons – Stiffness muscle = myoblasts – Stiffness bone = osteoblasts

8. Cancer Uncontrolled growth (proliferation) Invasion into surrounding tissues Metastasis (spread to other areas in body) Key terms: Malignant Proto-oncogene Oncogene Tumor suppressor gene

16. Thought questions Is DNA mutation necessary for cancer? Could cancer occur only by manipulating the microenvironment? If you took a piece of normal tissue and inserted it inside a tumor, what would happen? If you infect a chicken embryo with a cancer-causing virus, and the chicken grew up cancer-free, would you assume the chicken’s cells were cured of cancer? How might we test ways to see if certain microenvironments can stop cancer from growing?