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Vaccine against Tumour Spread?




Original article fromSTEM CELLS

"Preventive Cancer Stem Cell-Based Vaccination Reduces Liver Metastasis Development in a Rat Colon Carcinoma Syngeneic Model"

Cancer stem cells (CSCs) represent a minor population of self-renewing cells that fuel tumour growth and have recently been identified in solid tumors, including those in the colon (O'Brien et al, Ricci-Vitiani et al and Visvader and Lindeman).    Colon carcinoma is the second most common cause of cancer-related morbidity due, in part, to the appearance of metastases in the liver in 50%–60% of patients (Steele and Ravikumar).   In a recent study published in Stem Cells, researchers from the group of Valérie Pierrefite-Carle at the Université de Nice Sophia Antipolis, Nice, France, using a rat model of colon carcinoma,  demonstrate that a preventive vaccination generated using a CSC lysate can protect against the development of this liver metastasis, suggesting that CSC-based vaccination could be an efficient treatment to reduce tumour relapse in colon carcinoma (Duarte and Momier et al).

Initially, Aldh1, a promising CSC marker (Huang et al and Levi et al),  was used to sort the rat PROb colon carcinoma cell line, giving a population of around 3% Aldh1Hi CSCs which were able to grow as neurospheres.   Subcutaneous injection of Aldh1Hi CSCs into syngeneic rats gave rise to tumours within 30 days; however the injection of Aldh1Lo cells also gave rise to tumours at a similar frequency.   Dissociating Aldh1Hi tumours followed by in vitro culture led to the disappearance of non-tumour cells and the exponential growth of tumour cells as neurospheres.   Sorting these surviving cells on Aldh1 revealed a 10-fold increase in the percentage of Aldh1Hi cells compared to the PROb cell line, and after injection into the liver lobes of syngeneic rats (as to model a potential metastasis from a primary tumour), Aldh1Hi cells gave rise to tumours at 4.5 months, whereas rats injected with Aldh1Lo cells did not present any signs of tumor development.   Overall this suggests that this Aldh1Hi cell population was enriched for CSCs which were then used, alongside the initial PROb cell line, to prepare a vaccine using freeze-thaw cell lysates.   Mass spectrometry found each lysate to be different, suggesting that CSCs express specific antigens that could be taken advantage of.   Interestingly, of 142 proteins identified in the lysates, only 4 were found specifically in the Aldh1Hi lysates (HSP27, Aldose Reductase, 40s ribosomal protein S16 and Serum albumin precursor).   Comparison of the effectiveness of the vaccines to stop liver metastasis was examined through inoculating mice with either vaccine followed by the injection of PROb colon cancer cells into the left lobe of the liver.   Excitingly, although the PBS-vaccinated (10/10) and PROb-vaccinated rats (8/10) developed tumours, tumourigenesis was reduced (5/10) in the Aldh1Hi-vaccinated mice, while tumour volume was vastly decreased in both cell-vaccinated groups.

This study represent an exciting step forward in cancer stem cell based anti-cancer therapeutics; in this case the reduction in liver metastasis after a primary colon tumour.   Advancement of this type of study into other tumour-metastasis models could be potentially beneficial for the generation of multiple vaccines to be used alongside conventional anti-tumour therapies, if CSC markers can be reliably identified in solid tumours.   Further analysis of the proteomic makeup of several CSC populations could however lead to the discovery of a shared pro-tumourigenic peptide pattern allowing the generation of a single vaccine for administration to sufferers of multiple types of tumours.



Huang EH et al.
Aldehyde dehydrogenase 1 is a marker for normal and malignant human colonic stem cells (SC) and tracks SC overpopulation during colon tumorigenesis.
Cancer Res 2009; 69: 3382–3389.

Levi E et al.
Combination of aging and dimethylhydrazine treatment causes an increase in cancer-stem cell population of rat colonic crypts.
Biochem Biophys Res Commun 2009; 385: 430–433.

O'Brien CA et al.
A human colon cancer cell capable of initiating tumour growth in immunodeficient mice.
Nature 2007; 445: 106–110.

Ricci-Vitiani L et al.
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Nature 2007; 445: 111–115.

Steele G, Jr., Ravikumar TS.
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Visvader JE, Lindeman GJ.
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Nat Rev Cancer 2008; 8: 755–768.



STEM CELLS correspondent Stuart P Atkinson reports on those studies appearing in current journals that are destined to make an impact on stem cell research and clinical studies.