As discussed elsewhere, stem cells or cells derived from them will inevitably play a key role in restoring function after spinal cord injury (SCI). Since funding some of the first SCI-focused stem-cell research as PVA’s research director in the mid-1990’s, I’ve been amazed how many programs have emerged throughout the world which transplant stem cells from various sources into individuals with SCI.

However, to fully appreciate their healing ability, understand that the regenerative impact of these cells is not just from those externally transplanted into the patient. From conception until death, they are the cells of renewal and regeneration inherent within us all.

Stem and progenitor cells are found in most tissues, including the central nervous system (i.e., brain & spinal cord). Sometimes, they are involved in ongoing tissue maintenance, such as the bone-marrow’s production of blood-cell-replenishing stem cells; in other tissues, they are quiescent and need to be coaxed into action by appropriate stimuli. In the case of SCI, injury may mobilize dormant spinal-cord stem-cells into action.

The function of our endogenous stem cells can be positively or negatively influenced by numerous therapies. For example, acupuncture and hyperbaric oxygen therapy - both of which have been used to treat SCI – have been claimed to stimulate their expression. In contrast, the focus of this article, chemotherapy may be more toxic to CNS stem cells than the targeted cancer cells. As a result, it can sabotage the much needed and desired CNS-regenerative potential in individuals with SCI - even long after the chemotherapy.  

In brief, stem and progenitor cells encompass a continuum of cell types that transform into our end-product tissue. As our CNS develops, embryonic stem cells generate more specialized tissue-specific neural stem cells. In turn, these tissue-specific stem cells can differentiate into neuron- or glial-restricted precursor cells, the former with the potential to generate neurons and the latter into CNS support cells called oligodendrocytes and astrocytes. Especially important for this discussion, oligodendrocytes generate the insulating myelin sheaths that enwrap axons and are needed for signal transmission. These distinctions between different cell types are important because chemotherapy is more toxic to some of the precursor cell populations than others.

Stem-Cell Differentiation (From Stem Cell Now, CH Scott, 2005)

Chemotherapy

More than half of cancer patients receive chemotherapy. Although the research discussed below challenges the assumption, chemotherapeutic agents have been generally thought to target rapidly growing, dividing cells, like cancer cells.

Because chemotherapy is administered systemically, it eradicates cancer cells that have spread throughout the body, but, as a result, the whole body is vulnerable to potential adverse side effects. Although the blood-brain barrier may limit somewhat their infusion into the CNS, cancer drugs do, nevertheless, cross this barrier, often producing persistent, long-term cognitive deficits. It has been thought that chemotherapy especially affects brain areas associated with learning and memory, such as the stem-cell-rich hippocampus, but there is also substantial evidence of damage to myelinated regions of the brain (white matter).

Many studies have documented chemotherapy’s neurotoxicity, especially with high-incidence cancers. For example, 50% of breast-cancer patients may have cognitive impairments a year after chemotherapy was stopped. Even 3-6 years later, breast-cancer survivors have more auditory-processing dysfunction than age-matched controls.

Chemotherapy & CNS Stem Cells

Dr. Mark Noble and his University of Rochester (NY) colleagues have recently carried out ground-breaking studies that help us understand more clearly chemotherapy’s neurotoxicity. These studies have evaluated the impact of various commonly used cancer drugs on CNS progenitor cells grown in culture (in vitro) and in mice (in vivo). The cell-culture studies indicated that clinically relevant levels of commonly used drugs were more lethal to CNS-progenitor cells than they were for a variety of cancer cell types.

The progenitor cells that evolved into myelin-producing oligodendrocytes (see illustration) were especially sensitive to the toxic effects of chemotherapy. In addition, non-dividing oligodendrocytes themselves were also particularly vulnerable, a finding which challenges the widely held belief that chemotherapy only targets dividing cells. Although less sensitive to chemotherapy than oligodendrocytes, astrocytes (the other key glial support cell) were still as susceptible as the targeted cancer cells.

Chemotherapy also changed the composition of surviving cells. Specifically, the oligodendrocyte precursor cells would not renew themselves through cell division but would differentiate into oligodendrocytes. The investigators stated “Such a loss of dividing cells would compromise the ability of dividing progenitor cells to contribute to repair processes, and could also contribute to long-term or delayed toxicity reactions.”

Confirming these results, progenitor cells and oligodendrocytes were compromised in vivo when mice were systemically given these cancer drugs. Short-term systemic administration of one of these drugs was shown to cause “both acute CNS damage and …progressively worsening damage to myelinated tracts of the CNS…” Consistent with the observations in breast-cancer survivors, this damage correlated with a delayed loss of function in the mice as measured by auditory dysfunction.

What about Radiation?

Although beyond the scope of this article, evidence also suggests that neural precursor cells are extremely sensitive to radiation, the other twin pillar of cancer treatment. Once again challenging the assumption that therapy preferentially targets proliferating cells, radiation is especially lethal to quiescent, non-dividing neural precursor cells.

Conclusion

Noble et al stated that the “prevalence of cancer in the world’s populations means that the total number of individuals for whom adverse neurological changes are associated with cancer treatment is as great as for the more widely recognized neurological syndromes.” In other words, the leading cause of neurological dysfunction may not be disease (e.g., MS) or injury (SCI or head injury) but that brought about by medicine (i.e., iatrogenic).

Although chemotherapy’s risk-benefit tradeoffs have always challenged the physician’s pledge to first do no harm, this is an especially sobering assessment that underscores the need to develop new treatment options. In addition, chemotherapeutic agents are increasingly used to treat individuals with autoimmune disease, including MS. It is thus essential to know whether chemotherapy has adverse effects on patients with MS receiving such treatment.

On the positive side, Noble’s pioneering work provides invaluable insights on how we can assess such options with respect to their ability to preserve the body’s neurological regenerative potential.

KEY REFERENCES

1)     Meyers CA. How chemotherapy damages the central nervous system. J Biol 2008; 7.

2)     Dietrich J, et al. CNS progenitor cells and oligodendrocytes are targets of chemotherapeutic agents in vitro and in vivo. J Biol 2006; 5.

3)     Han R, et al. Systemic 5-flurouracil treatment causes a syndrome of delayed myelin destruction in the central nervous system. J Biol 2008; 7.

4)     Encinas, et al. Quiescent adult neural stem cells are exceptionally sensitive to cosmic radiation. Exp Neurol 2008; 210.

5)     Moss RW, Questioning Chemotherapy. Equinox Press, 2004.

Adapted from article appearing in October, 2008 Paraplegia News (For subscriptions, call 602-224-0500) or go to www.pn-magazine.com. 

 TOP