Skin-cancer stem cells Research(from Nature)

Skin-cancer stem cells outwitted

Skin-cancer stem cells secrete a factor that organizes a blood-supply system to fuel tumor growth. But the same factor has another sinister function – it stimulates the stem cells to propagate uncontrollably.

The most frequently diagnosed cancers in industrialized countries are non-melanoma skin cancers, including squamous-cell and basal-cell carcinomas.
Like most other solid tumors, squamous-cell carcinomas harbour a subset of cells known as cancer stem cells which initiate and propagate the tumor by a hitherto unknown mechanism. On the Research ‘Avascular niche and a VEGF밡rp1 loop regulate the initiation and stemness of skin tumors’, Beck and colleagues reveal that these cells secrete copious amounts of a growth factor that uses a two-pronged strategy to ensure that tumor growth continues indefinitely. They show that obstructing this dual activity causes the pool of cancer stem cells to shrink and the tumor to regress. The growth factor that Beck et al. find to be secreted in large quantities by skin cancer stem cells (CSCs) is VEGF. In a process known as angiogenesis, VEGF attracts endothelial cells that line blood vessels and stimulates their proliferation, creating a vascular network to supply the growing tumor with essential oxygen and nutrients5. VEGF signals to endothelial cells by binding to a specific receptor, known as VEGFR2, on the cell membrane (Fig. 1).
When the authors used antibodies against VEGFR2 to block the receptor in mice with skin tumors, this not only prevented angiogenesis, but also caused the pool of CSCs to decrease, which retarded tumor growth. CSCs were also able to transduce signals from VEGF with the help of a transmembrane co-receptor called neuropilin-1 (Nrp1) that works with the primary VEGF receptor (VEGFR). Through Nrp1, VEGF stimulates the expression of genes that are enriched in CSCs for example, those responsible for cell proliferation, such as cyclin D1, as well as genes such as Sox2 that confer the unique features of stem cells, or 쁲temness. Cutaneous CSCs therefore renew themselves in response to the VEGF they secrete a cell-autonomous, self-communicating mechanism referred to as an autocrine loop (Fig. 1). Strikingly, VEGF causes the CSC pool to increase even in the absence of a new blood-supply network. The dual response of CSCs to VEGF could explain these cells ability to both initiate and propagate tumors. These same pathways may enable CSCs to re-form a complete carcinoma when transplanted in low numbers, or even as single cells, in experimental mouse models of skin cancer and allow them to leave a patient셲 primary tumor and establish a metastatic tumor in a distant organ. Inhibiting VEGF signalling has already been shown to reduce squamous tumor initiation in vivo. And, as Beck et al. show, selective inhibition of VEGF signalling in CSCs, but not vascular cells, causes a drastic drop in CSC population and regression of the tumor.
The CSCs in squamous tumors that Beck et al. studied were predominantly in niches closely associated with the underlying endothelial cells. Leukaemia and braintumor stem cells are also often found side by side with vascular cells. There is strong evidence that CSCs 쁱ead factors released by neighbouring endothelial cells and that these factors are necessary for CSC maintenance (paracrine communication) perhaps working in synergy with the autocrine signalling through CSC-derived VEGF to sustain tumor stemness (Fig. 1).


These findings raise several interesting questions. For instance, heterogeneous populations of CSCs have been described3 in squamous-cell carcinomas that have comparable tumor-promoting potential but different proliferation rates. CSC heterogeneity is also evident in leukaemias and in solid tumors such as lung carcinomas. Are different CSC subtypes localized close to the vascular niche? Do other tumor types rely on the VEGF autocrine loop? Does Nrp1 act alone or does it cooperate with different primary VEGF receptors? One might also ask whether CSCs are equally dependent on autocrine VEGF and on communicating with neighbouring endothelial cells for their self-renewal, and whether VEGF is still as important in the later stages of cancer as it is in the initial stages.
Developing strategies that precisely target the self-sustaining mechanism of CSCs rather than blanket prevention of angiogenesis might be therapeutically useful. One adverse side effect of anti-angiogenic cancer therapies is the deprivation of oxygen in tumors, which paradoxically enhances their metastatic potential. Therapies that preferentially inhibit VEGF signalling in CSCs for instance by preventing interaction between Nrp1 and VEGF might selectively prevent stem-cell self-renewal without creating pro-metastatic oxygen shortage.
Although most of the vascularly secreted paracrine factors that affect CSC self-renewal are yet to be identified, blocking their activity might also selectively eliminate CSCs with little anti-angiogenic effect. Beck and colleagues promising findings warrant further investigation into the molecular mechanism and therapeutic potential of blocking the autocrine VEGF/Nrp1 loop.
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Research Paper ‘Avascular niche and a VEGF밡rp1 loop regulate the initiation and stemness of skin tumors’

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