Antibodies targeting cancer stem cells: a new paradigm in immunotherapy?

Abstract

Antibody targeting of cancer is showing clinical and commercial success after much intense research and development over the last 30 years. They still have the potential to delivery long-term cures but a shift in thinking towards a cancer stem cell (CSC) model for tumor development is certain to impact on how antibodies are selected and developed, the targets they bind to and the drugs used in combination with them. CSCs have been identified from many human tumors and share many of the characteristics of normal stem cells. The ability to renew, metabolically or physically protect themselves from xenobiotics and DNA damage and the range of locomotory-related receptors expressed could explain the observations of drug resistance and radiation insensitivity leading to metastasis and patient relapse.Targeting CSCs could be a strategy to improve the outcome of cancer therapy but this is not as simple as it seems. Targets such as CD133 and EpCAM/ESA could mark out CSCs from normal cells enabling specific intervention but indirect strategies such as interfering with the establishment of a supportive niche through anti-angiogenic or anti-stroma therapy could be more effective.This review will outline the recent discoveries for CSCs across the major tumor types highlighting the possible molecules for intervention. Examples of antibody-directed CSC therapies and the outlook for the future development of this emerging area will be given.

Keywords: antibody; cancer; stem cell; targeting; therapy.

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Figure 1

Cancer stem cell-related antibody targeting. Tumors are proposed to contain a CSC niche which supports the small number of CSCs through cell-matrix interactions. These CSCs, bearing receptors for adhesion and self-renewal give rise to the bulk tumor cells which also have tumor-associated antigens as well as daughter CSCs. Metastatic CSCs may arise when receptors involved in invasion and homing are expressed. Growth factors are expressed which stimulate tumor angiogenesis, migration to metastatic sites and promote proliferation and protection within existing niches. Chemotherapy drugs have poor access to the tumor. Factors which could be modulated by antibody intervention are shown as well as the use of stem-cell renewal-specific drugs for a combinatorial approach to CSC therapy. Refer to the key for the types and examples of receptors and CSC-factors.