Radiation Biology

Cancer stem cell (CSC)

A subpopulation of cells within tumor that have the ability to self-renew and to cause heterogenous lineages of the cancer cell
Believed to be in G0 phase of cell cycle.
No ideal marker for CSC but CD133 surface expression is commonly used to identify CSC

Understanding Radiation Biology:


Cell Cycle	G1 Phase: The cell is committed to division and metabolic changes prepare cell for division S Phase: DNA synthesis duplicates genetic material. G2 Phase: Metabolic changes that assemble necessary cytoplasmic material needed for mitosis and cytokinesis M Phase: Nuclear Division (mitosis) followed by cell division (cytokinesis)
Radiation Induced DNA Damage	1. Direct Damage = Kinetic energy (incident photon) is transferred to orbital electron of water molecule leading to Free radical formation + Ejecting electron (now known as secondary electron, leads to direct damage to DNA) 2. Indirect Damage = 75% of damage, when a photon strikes water molecule within 2-4 nm of DNA strand.
Repair	1. Most Damage - Sublethal Single DNA strand break which accumulate through prolonged exposure 2. Free radical Scavengers (like Glutathione) play a major role in determining the extent of initial radiation induced DNA damage 3. Repair of sublethal damage can occur by various mechanism like Survivin, an Apoptosis inhibitor (Woodward et al.) act on DNA DSB repair Autophagy (CD133+) 4. Dose Fractioning is done to over come these problems but therapeutic resistance is multifactorial and complex and depends on the fact how CSC handle Radiation Induced DNA damage.
Reassortment	1. Different cell groups are at different stage of cell cycle Most sensitive phase - G2 and mitosis Most resistant phase - S phase 2. Dose Fractioning can allow S phase cell to enter more sensitive phase of cycle. More cycling cell leads to more Radio-sensitivity 3. TARE optimises this problem by providing prolonged brachytherapy at low exposure.
Repopulation	1. Most common reason for the failure of conventional fractioned course of radiation therapy. 2. Ionizing Radiation cause CSC to switch . from Asymmetric type of cell division formation of 1 Daughter stem cell + 1 lineage committed progenitor cell or Symmetric type of cell division forming 2 Daughter stem cells 2. TGF-Beta pathway = Anti-proliferative pathway Decreased TGF levels activates the Notch pathway = Self renewal 3. Impact tumor genotype and architecture leading to Aggressive recurrence and non-response. 4. Fractioning of dose provides therapeutic advantage over single-dose radiotherapy
Reoxygenation	1. Sufficient Oxygen Tension (>10 mmHg) is needed for any form of radiation to be absorbed and interact with DNA 2. Microenvironment is dynamic with ever changing oxygen and pH gradient 3. Region of - Acute Hypoxia (intermittent vessel closure) - Chronic Hypoxia (due to limitation of oxygen diffusion) 4. Perivascular niche [Hypoxic (Intermittent) cells] are 2-3 times more resistant to radiation (radioprotective mechanism incompletely understood) 5. Therefore reoxygenation between dose fractions is generally believed to improve efficacy of radiation treatment. 6. Chronic hypoxia in cell also make them radiosensitive by decreasing DNA repair 7. Low embolic nature of TARE causes subtotal arterial occlusion and un-compromised portal perfusion leads to continued hepatic oxygenation with sustained radiation exposure.

References

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