Biomedical Engineering Reference
In-Depth Information
therapeutic intervention may be applied to specifically target and deplete
mCSCs leading to greater efficacy in treatment. Summarized below are several
such points and potential approaches based on what is currently known about
them.
6.1 Targeting the (Pre-)metastasis Niche
Tissue-specific tropisms and interactions of mCSCs can be exploited with
appropriate therapeutics. The metastatic microenvironment affects homing,
adhesion, and proper functions of mCSCs, including self-renewal and differ-
entiation, any of which could prove useful pathways to target at the molecular
level using inhibitors or competitors of key factors. After it was shown that
secretion of VEGF and PlGF initiated remodeling of pre-metastatic niches, it
was also shown that inhibiting these factors with specific antibodies reduced
metastasis (Kaplan et al. 2005). It has been known for some time that VEGF is
an angiogenic factor associated with malignancy. The possibility that the under-
lying mechanism involves mCSCs is still debated (Jain 2001; Lin and Sessa
2004). Nonetheless a VEGF antibody drug (bevacizumab) is currently in clin-
ical trials based on its anti-angiogenic properties (Hurwitz et al. 2004). It will be
an important step in understanding mCSCs to see if it can increase survival in
patients with recurrent tumors that have proven refractory to standard
treatment.
As niches provide anchor sites for mCSCs this adhesion could also be
blocked. CD44 surface receptor inhibition leads to reduction of engraftment
of cancer cells in acute myelogenous leukemia when injected directly into bone
marrow (Jin et al. 2006). CD44 has also shown similar effects in chronic
myelogenous leukemia (Krause et al. 2006) and is important as a marker of
Fig. 3 Traditional and CSC-based approaches in cancer treatment. Chemotherapy and
radiation are standard treatments for tumors but do not specifically deplete CSCs. A tumor
comprises a small subset of tumorigenic, self-renewing CSCs and a bulk of cancer cells
incapable of propagating new tumor growth. mCSCs break away from the malignant
tumor to cause metastasis. Use of non-specific radiation or chemotherapy may shrink the
tumor but does not deplete more chemoresistant CSCs. Over time CSCs repopulate the tumor
through proliferation and may be more aggressive/invasive than the original tumor (referred
to as rebound effects) as radiation/chemotherapy may select for mCSCs due to the coupled
activity of metastasis and chemoresistance encoded in certain dual-functional genes. mCSCs
proceed to colonize secondary tissue and produce recurrent metastasis (upper panel). Thera-
pies that specifically target and deplete CSCs may not have a dramatic effect on tumor size by
current standards, but do abrogate long-term tumorigenic potential. Over time the bulk of the
tumor shrinks as tumor cells are eliminated through natural attrition or conventional che-
motherapies and are not replaced. New drugs are needed to accomplish such targeted therapy
and new clinical assays are also essential for measuring the success of these novel therapies
