Cell Differentiation and Cancer Stem Cells

Differentiated Cells

Differentiated cells are assigned to help the whole organism.

Cancer Cell Characteristics

Cancer cells exhibit:

  • Genetic alterations: Abnormal abilities due to genetic changes.
  • Uncontrolled division: Irresponsive to external signals and internal checkpoints.
  • Evasion of apoptosis: Avoidance of programmed cell death induction.
  • Loss of cell contact sensitivity: Evidenced by movement and piling of cells in vitro.

Tumor Cell Heterogeneity

Initial assumptions of tumor homogeneity have been challenged by evidence indicating:

  • Heterogeneous genetic regulation: Variation among tumor cell populations.
  • Normal Genetic Programs: Tumor cells still utilize normal operating genetic programs.

Proliferative Potential and Differentiation

The proliferative potential of a cell is inversely related to its degree of differentiation.

  • Cells that are more differentiated are less likely to become other cell types, reducing the drive to divide.
  • Replicative Potential: Decreases with increased differentiation.

A Journey to Differentiation starting at the Beginning

Figure 21-2 Molecular Biology of the Cell (© Garland Science 2008)

Gastrulation

  • During gastrulation, cells differentiate into three primary germ layers:
    • Ectoderm: Forms the pre-epidermis and nervous system.
    • Endoderm: Forms the pre-gut tube, lung, pancreas, and liver.
    • Mesoderm: Forms muscles, connective tissue, blood, and kidneys.

Allocation of Sea Urchin Cell Types

Figure 22-3 Molecular Biology of the Cell (© Garland Science 2008)

  1. Ectoderm -> 1.Epidermis
  2. Endoderm -> 1.Gut & Appendages (lung, liver, ect.)
  3. Mesoderm -> 1.Muscles, Connective Tissue, & other components

Post-Gastrulation early amphibian fetus

  • A sheet of ectoderm on the outside
  • A tube of endoderm on the inside
  • Mesoderm in between

Essential Cell Processes in Multicellular Development

Figure 22-1 Molecular Biology of the Cell 7e (© Garland Science 2020)

Restriction of Cellular Potential

  • The potential of cells to become other cell types is progressively restricted.
    • Totipotent: Potential to become any cell in the organism.
    • Pluripotent: Potential to become several cells in the organism.

Causes of Cell Differentiation

A. Spatial Signaling
B. Temporal Signaling
C. Cell Contact
D. Cell Division
E. All of the above

Signal Induced Differentiation

Signals Generate Complex Patterns

  • Signals create memory and a predictable choice when given a decision.
  • Signals are combinatorial.

Spatial Patterning through Inductive Signaling

  • Paracrine signals from a cohort of cells affect the modulation of gene expression in neighboring cells.

Morphogens and Inductive Signal Gradients

Figure 22-15 Molecular Biology of the Cell (© Garland Science 2008)

  • Morphogens are inductive signal gradients that are both spatial and temporal.

Paracrine Signaling and Lateral Inhibition

Figure 22-12 Molecular Biology of the Cell (© Garland Science 2008)

  • Lateral inhibition results in cellular asymmetry.

Lateral Inhibition in Drosophila Bristle Formation

Figure 21-34 Molecular Biology of the Cell 7e (© Garland Science 2022)

  • Delta and Notch proteins play a central role in cell contact signaling.

Major Signaling Molecules in Development

Table 22-1 Some Signal Proteins That Are Used Over and Over Again as Inducers in Animal Development
Table 22-1 Molecular Biology of the Cell (© Garland Science 2008)

Division Induced Differentiation

Sister Cell Differentiation

Figure 22-11 Molecular Biology of the Cell (© Garland Science 2008)

  1. Asymmetric division: sister cells born different
  2. Symmetric division: sister cells become different as a result of influences acting on them after their birth

Tissue Homeostasis and Cell Replenishment

Figure 22-1 Molecular Biology of the Cell 7e (© Garland Science 2022)

  • Differentiated cells need to be replenished to establish tissue homeostasis.

Stem Cells

  • A stem cell can self-renew or differentiate.
  • Self-renewal of a pluripotent cell not specified for a certain cell type can theoretically have infinite division cycles.

Stem Cell Division and Lineage

  • Once a stem cell divides into a specified progenitor, the following lineages have limited cellular divisions.

Hematopoietic Stem Cells

Figure 22-12 Molecular Biology of the Cell 7e (© Garland Science 2022)

  • Give rise to several different types of blood cells.

Tissue-Specific Stem Cells

Responsible for replenishing certain tissues:

  • Stem cells require a specific niche to maintain proper division and spatial differentiation programs.

Stem Cell Orientation within Adult Tissue

  • Small population of stem cells in the basal cell layer of skin (Figure 23-3 Molecular Biology of the Cell (© Garland Science 2008))

Colon Cells Replenishment

Figure 23-21a Molecular Biology of the Cell (© Garland Science 2008)

  • Colon cells are consistently replenished.
  • Epithelial cell migration from "birth" at the bottom of the crypt to loss at the top of the villus (transit time is 3-5 days).
  • Rapidly dividing cells (cycle time 12 hours).
  • Slowly dividing stem cells (cycle time > 24 hours).

Proper Niche and Signaling for Differentiation

  • Proper niche and sequence of signaling can direct specific differentiation pathways.
  • Detached ES cells that are allowed to form embryoids can be directed with various signals to differentiate (Movie 22.2 - Molecular Biology of the Cell 7e).

Embryonic Cells and Niche Development

  • Embryonic cells transferred to a proper niche develop properly into an organism.

Embryonic Stem Cells and Teratoma Formation

  • Embryonic Stem cells placed in an abnormal niche form teratomas.
  • ES cells implanted on a late-stage animal embryo or adult tissue do not receive the correct sequence of cues for cell division and differentiation.

Naturally Occurring Teratomas in Humans

  • About 1 in 78 U.S. Women will acquire ovarian tumors.
  • Most (95%) of the ovarian tumor cases are benign.
  • 20% of ovarian tumors are unfertilized germ cell tumors known as mature teratomas.
  • Mostly benign but a rare (1-2%) can become malignant.

Ovarian Teratoma Characteristics

  • Have distinct differentiated cells; bone, teeth, hair, muscle, fat, and even thyroid tissue.

Tumor Cell Protein Expression

Figure 11.19 (A) The Biology of Cancer (© Garland Science 2023)

  • A selection of breast tumor cells acquired through Fluorescence Activated Cell Sorting (FACS).
  • Cells expressing membrane surface proteins.
    • 12% CD44 High and CD24 Low
    • The rest expressing CD44 High and CD24 High

Cancer Stem Cells

  • Injection of proposed cancer stem cell only able to form tumor.
  • 200 of the small subset of breast cancer cells injected into an immunocompromised mouse.

Wnt Pathway and Stem Cell Proliferation

Figure 23-24 Molecular Biology of the Cell (© Garland Science 2008)

  • Some Stem cells shown to have an active Wnt pathway
    • Active Wnt pathway = proliferation
    • Inactive Wnt pathway = no proliferation

Wnt Pathway Activation in Colorectal Cancer

Figure 23-24 Molecular Biology of the Cell (© Garland Science 2008)

  • Constitutive activation of Wnt pathway occurs in 90% of colorectal cancer
  • This is due to loss of the adenomatous polyposis coli (APC) gene

APC Loss and Tumor Formation

Figure 23-23 (part 1 of 2) Molecular Biology of the Cell (© Garland Science 2008)

  • Apc loss in differentiated or transit amplifying cells fail to form a tumor

APC Loss and Tissue-Specific Stem Cells

Figure 23-23 (part 2 of 2) Molecular Biology of the Cell (© Garland Science 2008)

  • Apc loss in tissue-specific stem cells form a tumor: Evidence for a colorectal cancer stem cell

Transgenic Cancerous Tumor Mouse Model

  • A transgenic cancerous tumor mouse model shows a dependency on altered stem cells.
  • When expressing the ras oncogene in differentiated keratinocytes of the hair follicle, benign papillomas form.
  • Whereas expression of the ras oncogene in keratinocyte stem cells, form malignant carcinomas.

Cancer Stem Cell Potential

AML (Acute Myeloid Leukemia):

  • Only 1 in 1,000,000 transfer the leukemia
  • Express the same cell surface markers
  • CD34+/CD38-

Breast Cancer:

  • Sub-population have 10 to 50-fold ability to cause tumors in animal models
  • Cell surface markers
  • CD44+/ CD24-/low

Colon, Brain, & Prostate Cancer:

  • Sub-population
  • Over-express surface marker
  • CD133

Genetic Alterations and Stem Cell Induction

  • Genetic alterations can induce differentiated cells to become stem cells.
  • Known as induced pluripotent cells.
  • In 2006, co-expression of Oct4, Sox2, Klf4, & Myc could reprogram mouse fibroblasts into cells very similar to ES cells.
  • Suggest that mutations or abnormal activation of genes could reprogram a cancer cell in a differentiated focused lineage
  • Does this abolish the cancer stem cell theory?