Research Main » Cancer SC During Tumor Growth & Relapse After Therapy
Cancer stem cells during tumor growth and relapse after therapy
Some cancers contain cells with stem cells characteristics, and which are called cancer stem cells. We are using different approach to understand the mechanisms regulating cancer stem cell function during tumor growth and relapse after therapy.
Dual role of VEGF in regulating cancer stemness
Skin squamous cell carcinomas are amongst the most frequent cancers in humans. Recent studies suggest that skin squamous cell carcinoma, like many other human cancers, contain particular cancer cells, known as cancer stem cells, that present increased self-renewal potential that sustain tumor growth. Little is known about the mechanisms that regulate cancer stem cell functions.
To dissect the mechanisms that regulate cancer stem cells, we determined which genes are preferentially expressed by cancer stem cell of skin tumors. We found that VEGF, a molecule known to regulate the formation of new vessels, is expressed at high level by skin cancer stem cells, which are located in close contact to the blood vessels in a vascular niche. Administration of an antibody against VEGFR2 that decreases new blood vessel formation to mice presenting skin tumors results in a reduction of the pool of cancer stem cells leading to a reduction of the tumor size, demonstrating that vascular niche regulate skin cancer stem cell functions.
To determine whether VEGF secretion by cancer stem cells directly regulates the function of cancer stem cells, we genetically deleted VEGF specifically in tumour cells, and found that upon VEGF ablation, skin cancer stem cells were rapidly lost due to a defect in their renewal properties, leading to tumour regression.
We also found that Neuropilin 1, a VEGF receptor, is also highly expressed by skin cancer stem cells, and showed that Neuropilin 1 expression by cancer stem cells is critical to promote cancer stem cell renewal and tumour growth. In addition, we found that Neuropilin 1 is also essential for tumour formation, demonstrating the critical role of Neuropilin 1 during both cancer initiation and tumor growth.
Altogether this new study provides novel and important insights into the mechanisms by which VEGF controls tumour growth. VEGF signalling in endothelial cells is critical to sustain the formation of the vascular niche, promoting indirectly the renewal of skin cancer stem cells. Autocrine VEGF secretion by cancer stem cells acts also directly on cancer stem cells by a Neuropilin 1 dependent mechanism to promote cancer stem cell renewal and tumor growth. These results suggested that new therapies blocking VEGF and/or Neuropilin 1 functions in cancer cells might be more effective for the treatment of certain cancers compared to the therapeutic strategies blocking VEGF function only in endothelial cells.
Our study has been published in the Nature 2011 and was accompanied by a News and Views by Benitah.
Beck B, Driessens G, Goossens S, Youssef KK, Kuchnio A, Caauwe A, Sotiropoulou PA, Loges S, Lapouge G, Candi A, Mascre G, Drogat B, Dekoninck S, Haigh JJ, Carmeliet P, Blanpain C.
A vascular niche and a VEGF-Nrp1 loop regulate the initiation and stemness of skin tumours.
Nature. 2011 Oct 19;478(7369):399-403. doi: 10.1038/nature10525.
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Defining the mode of tumour growth by clonal analysis
One of the key questions in cancer is to understand how tumours grow. Recent studies suggest that cancer can be hierarchically organized as normal tissues containing cancer stem cells at the top of the cellular hierarchy. Cancer stem cells have been described in different human cancers including skin cancers. Cancer stem cells have been hypothesized to sustain tumour growth, to resist to chemo and radiotherapy and to be responsible for tumour relapse. Until now, cancer stem cells have been demonstrated by their ability to reform tumour upon transplantation into severely immunodeficient mice. These studies clearly show the potential of cancer cells in these experimental conditions but not necessarily reflect the actual fate of tumour cells in their native environment, and the existence of cancer stem cells during unperturbed tumour growth remained unproven.
In this study, we made use of clonal analysis to unravel the mode of tumour growth in vivo in its natural environment. To this end, we used a genetic labelling strategy that allows individual tumour cells to express the YFP reporter gene and follow their fate as well as their progeny over time at different stages of tumour progression. Interestingly, we found that in benign skin tumours, the majority of tumour cells have limited proliferative potential, while only a minority have the capacity to persist long term and divide rapidly, giving rise to progeny that occupy a big part of the tumour, consistent with the marking of long lived cancer stem cells.
Quantitative analysis of clonal fate data supports the existence of rapidly cycling cancer stem-like cells and a second population of more slowly cycling committed progenitors, mirroring the composition, hierarchy, and fate behaviour of the normal epidermis. Such behaviour is shown to be consistent with double-labelling experiments and detailed clonal fate characteristics. By contrast, clonal dynamic in invasive squamous cell carcinoma is consistent with emergence of a single CSC population with limited potential for terminal differentiation. This study presents the first experimental evidence for the existence of CSC during unperturbed solid tumour growth.
Our study has been published in the August issue of Nature 2012 and was accompanied by a News and Views by RJ Gilbertson and TA Graham.