Human CD271-Positive Melanoma Stem Cells Associated with Metastasis Establish Tumor Heterogeneity and Long-term Growth

Abstract

Human melanoma is composed of distinct cell types reminiscent of neural crest derivatives and contains multipotent cells that express the neural crest stem cell markers CD271(p75 NTR ) and Sox10. When isolated from solid tumors by using a method that leaves intact cell surface epitopes, CD271-positive, but not CD271-negative, cells formed tumors on transplantation into nude or nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice. These tumors fully mirrored the heterogeneity of the parental melanoma and could be passaged more than 5 times. In contrast, in more immunocompromised NOD/SCID/IL2rg null mice, or in natural killer cell-depleted nude or NOD/SCID mice, both CD271-positive and CD271-negative tumor cell fractions established tumors. However, tumors resulting from either fraction did not phenocopy the parental tumors, and tumors derived from the CD271-negative cell fraction could not be passaged multiple times. Together, our findings identify CD271-positive cells as melanoma stem cells. Our observation that a relatively high frequency of CD271/Sox10-positive cells correlates with higher metastatic potential and worse prognosis further supports that CD271-positive cells within human melanoma represent genuine cancer stem cells. Cancer Res; 71(8); 3098-109. Ó2011 AACR.

Mixed versus pure variants of desmoplastic melanoma: a genetic and immunohistochemical appraisal

“…13 CD271 (p75NTR) is a neural crest stem cell marker expressed in melanoma cells, which is associated with higher metastatic potential and worse prognosis. 15 In the current study, nestin and CD271 stained 86 and 65%, respectively, of all cases of desmoplastic melanoma with no statistically significant differences noted in the two variants, indicating that the populations of stem cells harbored appear to be similar in the two subtypes. Similar findings were obtained with respect to expression of SOX10, which stained 91% of cases in the current series with no significant difference between the two subtypes.…”

“…KIT was investigated on the basis of the rationale that melanomas lacking BRAF mutations may have mutations or copy number alterations in c-KIT. 12 Immunohistochemical markers included the following: nestin, an intermediate filament protein, a melanocyte stem cell marker and a marker for melanoma-initiating cells, associated with poor prognosis in conventional melanoma; 13 clusterin, an 80-kDa glycoprotein of undefined biological significance shown to be significantly increased in desmoplastic melanoma; 11 SOX10, a neural crest stem cell marker, expressed in melanocytes, specifically, strongly expressed by desmoplastic melanomas; 14 CD117, a stem cell growth factor receptor encoded by the KIT gene, a receptor tyrosine kinase involved in cell survival and proliferation of melanocytes; CD271 (p75NTR), a neural crest stem cell factor, which has been shown to correlate with higher metastatic potential and worse clinical outcomes in melanoma; 15 and Ki-67 protein, a marker of cellular proliferation, which is expressed during of all phases of cell cycling (G1, S, G2 and mitosis), but absent during the resting phase. 16 …”

Tumorőssejtek szerepe a melanoma progressziójában és heterogenitásában

“…A CD271 + melanomasejtek rendkívül nagy tumoriniciáló és metasztázisképző hajlammal bírnak, több egymást követő xenotranszplantáción keresztül is tumorigének [44]. Ráadásul a létrehozott tumorokon belül melanocyticus, glialis, simaizom-és neuronszerű sejtvonalak fejlődtek ki, amelyek a CD271 + tumorok multipotenciáját indikálják.…”

Cancer Stem Cells in Tumor Heterogeneity

“…Compelling evidence in support of the cancer stem cell hypothesis demonstrate that putative cancer stem cells isolated from leukemias, breast cancers as well as gliomas, when xenotransplanted into immunocompromised mice give rise to cancers very similar to and containing all the different cell types of the original tumor (Lapidot et al, 1994;Al-Hajj et al, 2003;Lee et al, 2006). In contrast, non-stem cancer cells either give rise to no tumors at all or tumors that lack many key characteristics of the cancer observed in the patient (Lapidot et al, 1994 (Civenni et al, 2011). This study, however, also shed some further light on one of the major caveats of the predominant method to identify and define cancer stem cells by xenotransplantation (and as also discussed elsewhere in this review).…”

“…As discussed elsewhere, the most commonly used in vivo assays to study the biology of cancer stem cells come with several serious caveats (Quintana et al, 2008) (Civenni et al, 2011). It is thus likely that tumor models in immunodeficient mice, where tumors essentially lack key components of the normal tumor microenvironment, may never fully mimic human tumor biology.…”