BackgroundClear cell renal cell carcinoma (ccRCC) displays heterogeneity in appearance—a distinctive pale clear to eosinophilic cytoplasm; however, little is known about the underlying mechanisms and clinical implications. We investigated the role of these eosinophilic features in ccRCC on oncological outcomes and response to tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors (ICIs).MethodsOne-hundred and thirty-eight ccRCC cases undergoing radical surgery (cohort 1) and 54 metastatic ccRCC cases receiving either TKIs or ICIs (cohort 2) were included. After histological evaluation, all cases were divided into three phenotypes based on the eosinophilic features at the highest-grade area: clear, mixed, or eosinophilic type. Gene expression and immunohistochemical analyses were performed to explore the potential mechanisms of these phenotypes in cohort 1. Further, the association of the three phenotypes with the best objective response to TKI or ICI, clinical benefit (complete/partial response or stable disease), and overall survival (OS) was assessed in cohort 2.ResultsThe clear type was significantly associated with increased hypoxia as well as angiogenesis gene signatures compared with the eosinophilic type. Gene signatures and protein expression related to effector T cell and immune checkpoint molecules were elevated to a greater extent in the eosinophilic type, followed by the mixed and clear types. The mixed and eosinophilic types exhibited greater PBRM1-negativity and increased prevalence of the epithelial-mesenchymal transition gene signature than the clear type. In the mixed/eosinophilic types of cohort 2, significant clinical benefit was observed in the ICI therapy group versus the TKI therapy group (p=0.035), and TKI therapy vs ICI therapy was an independent factor for worse prognosis of OS (HR 3.236; p=0.012).ConclusionThe histological phenotype based on the eosinophilic features, which are linked to major immunological mechanisms of ccRCC, was significantly correlated with therapeutic efficacy.
Although the existence of cancer stem cells in intestine tumors has been suggested, direct evidence has not been yet provided. Here, we showed, using the multicolor lineage-tracing method and mouse models of intestinal adenocarcinoma and adenoma that Bmi1- or Lgr5- positive tumorigenic cells clonally expanded in proliferating tumors. At tumor initiation and during tumor propagation in the colon, the descendants of Lgr5-positive cells clonally proliferated to form clusters. Clonal analysis using ubiquitous multicolor lineage tracing revealed that colon tumors derived from Lgr5-positive cells were monoclonal in origin but eventually merged with neighboring tumors, producing polyclonal tumors at the later stage. In contrast, the origin of small intestine tumors was likely polyclonal, and during cancer progression some clones were eliminated, resulting in the formation of monoclonal tumors, which could merge similar to colon tumors. These results suggest that in proliferating intestinal neoplasms, Bmi1- or Lgr5-positive cells represent a population of cancer stem cells, whereas Lgr5-positive cells also function as cells-of-origin for intestinal tumors.
The murine intestine, like that of other mammalians, continues to develop after birth until weaning; however, whether this occurs in response to an intrinsic developmental program or food intake remains unclear. Here, we report a novel system for the allotransplantation of small intestine and colon harvested from Lgr5
EGFP-IRES-CreERT2/+; Rosa26
rbw/+ mice immediately after birth into the subrenal capsule of wild-type mice. By histological and immunohistochemical analysis, the developmental process of transplanted small intestine and colon was shown to be comparable with that of the native tissues: mature intestines equipped with all cell types were formed, indicating that these organs do not require food intake for development. The intestinal stem cells in transplanted tissues were shown to self-renew and produce progeny, resulting in the descendants of the stem cells occupying the crypt-villus unit of the small intestine or the whole crypt of the colon. Collectively, these findings indicate that neonatal intestine development follows an intrinsic program even in the absence of food stimuli.
We recently reported that the polycomb complex protein Bmi1 is a marker for lingual epithelial stem cells (LESCs), which are involved in the long-term maintenance of lingual epithelial tissue in the physiological state. However, the precise role of LESCs in generating tongue tumors and Bmi1-positive cell lineage dynamics in tongue cancers are unclear. Here, using a mouse model of chemically (4-nitroquinoline-1-oxide: 4-NQO) induced tongue cancer and the multicolor lineage tracing method, we found that each unit of the tumor was generated by a single cell and that the assembly of such cells formed a polyclonal tumor. Although many Bmi1-positive cells within the tongue cancer specimens failed to proliferate, some proliferated continuously and supplied tumor cells to the surrounding area. This process eventually led to the formation of areas derived from single cells after 1–3 months, as determined using the multicolor lineage tracing method, indicating that such cells could serve as cancer stem cells. These results indicate that LESCs could serve as the origin for tongue cancer and that cancer stem cells are present in tongue tumors.
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