Solid tumors are composed of heterogeneous cell populations which interact in complex networks. As is the case in developing organs, tumor cells interact with and in turn are regulated by these components in the microenvironment. Metastatic tumor cells also recreate complex cellular microenvironments at metastatic sites. Over 120 years ago Paget proposed the “seed and soil” hypothesis of tumor metastasis (40
). Reframed in a modern context, the “seeds” are the cancer stem cells and the “soil” is the rich microenvironment composed of diverse cell types which interact with tumor cells via cytokine networks. These networks regulate cancer stem cells and their progeny which form the tumor bulk. Elucidation of these pathways may provide new targets for therapeutic development. Examples include the cytokines IL-6 and IL-8, as well as their receptors IL6R and CXCR1. Blockade of these cytokine pathways reduce breast cancer stem cells in pre-clinical models (33
). Clinical trials utilizing IL-6 blocking antibodies have been initiated for the treatment of multiple myeloma with early encouraging results (41
). Furthermore, anti-IL-6R antibody, tocilizumab, has been approved for the treatment of arthritis (42
) with little clinical toxicity. The small molecule CXCR1 inhibitor, Reperaxin, has been developed to block rejection in renal transplant patients and early clinical trials suggest it is well tolerated. Phase I clinical trials combining this cytokine receptor/inhibitor with chemotherapy are being planned. NF-κB also represents an attractive therapeutic target. Preclinical studies suggest that the NF-κB inhibitor, parthenolide, was able to target leukemic stem cells and early stage clinical trials for the treatment of leukemia utilizing this agent are in progress. Together, these trials will indicate the feasibility of targeting cancer stem cells by blocking interaction of these cells with the tumor microenvironment.
The cancer stem cell model has important implications for clinical trial design. Currently, tumor response rate is determined by tumor size as described by Response Evaluation Criteria In Solid Tumors (RECIST). For many tumors regression does not correlate with increased patient survival (43
). Since cancer stem cells may constitute only a minor fraction of a tumor, agents which target this population may not produce tumor regression. In fact, stem cell targeting agents would be expected to have more dramatic effects in the adjuvant then advanced tumor settings (46
). This suggests that in advanced disease, it will be necessary to combine CSC targeting agents with debulking agents such as chemotherapy or radiation therapy. Time to tumor progression may prove a more useful clinical endpoint then tumor regression in these studies. However, since the non-stem cell fraction of tumors may still retain proliferative capacity, the criteria used to define tumor progression are important so that patients are not removed from treatments prematurely. The evaluation of CSC biomarkers such as CD44, CD133 and aldehyde dehydrogenase-1 in serial biopsies may provide a tool to access the efficacy of CSC targeting agents (47
). Circulating tumor cells (CTC) may also provide a valuable source of CSC populations for biomarker analysis. These assays will need to be able to capture circulating cancer stem cells which may not express antigens such as Ep-CAM which are currently used. The use of neoadjuvant trial design may prove particularly useful for assessing effects of CSC targeting agents since acquisition of tissue before and after treatment enables assessment of efficacy of CSC targeting. In addition, the effect of these agents on increasing the complete pathologic response rate (CPR) an accepted clinical endpoint, can be readily assessed. Ultimately, randomized trials will be required to determine whether successful targeting of CSCs improves patient outcome.