The hippocampus is the most common seizure focus in people. Within the hippocampus, aberrant neurogenesis plays a critical role in the initiation and progression of epilepsy in rodent models, but it is unknown whether this also holds true in humans. To address this question, we used immunofluorescence on control healthy hippocampus and surgical resections from mesial temporal lobe epilepsy (MTLE), plus neural stem cell cultures, and multi-electrode recordings of ex vivo hippocampal slices. We found that a longer duration of epilepsy is associated with a sharp decline in neuronal production, and persistent numbers in astrogenesis. Further, immature neurons in MTLE are mostly inactive, and are not observed in cases with local epileptiform-like activity. However, immature astroglia are present in every MTLE case and their location and activity are dependent upon epileptiform-like activity. Immature astroglia, rather than newborn neurons, therefore represent a potential target to continually modulate adult human neuronal hyperactivity.
We noted CD66 expression associated with clusters of cells which are spindle shaped, SMA+ve, podoplanin+ve, phalloidin high, fibronectin high, plakoglobin low, ki67-ve and CK10+ve at the migratory phase along with features of partial EMT. Further, TGFβ1 a well known regulator of EMT, positively correlated with CD66 expression. The additional CD49f+ve subset at the leading invading front of migration was SMA-ve, phalloidin low, fibronectin low, plakoglobin high, Ki67+ve and CK14+ve. These data are consistent with a role for CD66 cells in metastatic invasion with a collective cell migration process co-opting the CD49f subset. Our retrospective analysis of a cohort is consistent with a role for CD66 in metastasis. However, the broad analysis of CD66, CD49f and TGFβ1 expression with patterns of overall survival points to a possible protective effect particularly for local recurrences. Hence, future studies focussing on potential heterogeneity within the CD66 subset along with the possible role of isoforms and intra-cellular roles would be essential.
Cervical cancers, a malignancy associated with oncogenic papillomaviruses, remain a major disease burden in the absence of effective implementation of preventive strategies. CD66+ cells have previously been identified as a tumor propagating subset in cervical cancers. We investigated the existence, differentiation state and neoplastic potential of CD66+ cells in a pre-cancer cell line harboring HPV31b episomes. The gene expression profile of CD66High cells overlaps with differentiated keratinocytes, neoplastic mesenchymal transition, cells of the squamo-columnar junction and cervical cancer cell line derived spheroids. There is elevated expression of DNMT1, Notch1 and the viral gene product E1^E4, in CD66High cells. Thus CD66High cells, in the absence of differentiating signals, express higher levels of key regulators of keratinocytes stemness, differentiation and the viral life cycle respectively. We also find a striking association of neoplastic traits including migration, invasion and colony formation in soft agar with CD66High cells. These properties and a distinct G2M enriched cell cycle profile are conserved in cells from cervical cancers. Principally, using a precancerous cell line, we propose that CD66High cells have an intermediate differentiation state with a cellular milieu connected with both viral replication and neoplastic potential and validate some key features in pre-cancer lesions. Such pathophysiologically relevant systems for defining cellular changes in the early phases of the disease process provide both mechanistic insight and potential therapeutic strategies. Collectively, our data provides a rationale for exploring novel therapeutic targets in CD66+ sub-sets during cancer progression.
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