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Abstract: Background In advanced epithelial ovarian cancer (EOC), the peritoneum is the primary site of disease recurrence which occurs in >75% of patients despite complete cytoreductive surgery (CRS) and chemotherapy. Macroscopically undetectable remaining cancer cells are deemed to be a source for recurrent disease. We investigated characteristics of occult disease in biopsies of macroscopically normal peritoneum during CRS. Materials and methods We included 14 patients with advanced stage high grade serous ovarian cancer (HGSOC). Eleven patients had received neoadjuvant chemotherapy (NACT) and three patients were chemotherapy naïve. Each patient underwent three study-related peritoneal biopsies: 1) of a metastasis, 2) adjacent to a metastasis and 3) at distance from metastases. Cryostat sections were immunohistochemically stained for PAX8 and PanCK as markers of EOC cells and for CD31 as a marker for vascular and lymphatic endothelium. The sections were analyzed semi-quantitatively. Results Macroscopically normal peritoneum showed solitary PAX8-positive cells adjacent to and at distance from metastases in all patients. Thirteen percent of these PAX8-positive cells were found to be attached to the mesothelium and are presumably spread through intra-abdominal fluid. Eighty-seven percent of the solitary PAX8-positive cells were found in the stroma underneath the mesothelium, of which 59% were firmly attached to endothelium and 33% were found in the stroma. In most cases, no sign of proliferation of the solitary cells was observed. Only a few clusters of PAX8-positive cells were found. Chemotherapy did not affect these results. Conclusions Solitary PAX8-positive cells are present in the macroscopically healthy-looking peritoneum of all EOC patients investigated, irrespective of the distance to macroscopically-visible metastases and of previous treatment. The majority of these solitary cancer cells were attached to endothelium of capillaries, venules or lymphatic vessels. Their solitary character and lack of proliferation suggests a dormant state, which could explain why these cells are unaffected by neo-adjuvant chemotherapy.
Keywords: ovarian cancer, peritoneal metastasis, translational medical research, human pathology, PAX8, cancer recurrence
Published in DiRROS: 26.02.2025; Views: 138; Downloads: 100
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Abstract: Brain, the major organ of the central nervous system controls and processes most of body activities. Therefore, the most aggressive brain tumor – glioblastoma and metastases from other organs to the brain are lethal leaving the patients with very short time of survival. The brain tissue landscape is very different from any other tissues and the specific microenvironment, comprising stem cells niches and blood-brain barrier, significantly influences the low rate of glioblastoma metastasis out of the brain, but better accommodates brain-invading cancer. In contrast to low frequency (0.5%) of all glioblastoma metastases, 10%–45% of other primary cancers do metastasize to the brain. This review addresses general cellular and molecular pathways that are to some extent similar in both types of metastases, involving circulating tumor cells (CTCs) with cancer stem cells (CSCs) characteristics, and metastatic niches. The invasion is a dynamic process involving reversible epithelial-to-mesenchymal (EMT) cell process, creating a transient gradient state that is inter-connected with epigenetic plasticity of the metastasizing (m)CSCs. These cells can switch between stationary, low proliferating/dormant state to a migratory, mesenchymal-like state. Settling in their respective niches as dormant CSCs in the secondary organ is a common feature in all types of metastases. In glioblastoma metastasis, the malignant mGSC cells express markers of mesenchymal GSC subtype (MES-GSC), such as CD44 and YK-40 and their major obstacle seems to be propagating in the in various organs’ microenvironments, different from the niches that home GSCs in the primary glioblastoma. Focusing on one stromal component in the glioblastoma niches, the mesenchymal stem cells (MSCs), we report herein on their differential effects on glioblastoma cells, highly depending on their genetic subtype. On the other hand, in brain metastases, the major hindrance to metastatic progression of mCSCs seem to be crossing the blood-brain-barrier. Novel therapeutic approaches for brain metastases from various cancer types are advancing slowly, and the general trends involve targeting metastatic sub-clones and selective determinants of their niches. The update on the four most common brain metastases from lung, breast, melanoma and colorectal carcinoma is presented.
Keywords: glioblastoma, cancer stem cells, invasion, metastasis, tumor microenvironment
Published in DiRROS: 06.08.2024; Views: 568; Downloads: 326
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Abstract: Metastatic progression of breast cancer is still a challenge in clinical oncology. Therefore, an elucidation how carcinoma cells belonging to different breast cancer subtypes realize their metastatic capacities is needed. The aim of this study was to elucidate a similarity of activated molecular pathways underlying an enhancement of invasiveness of carcinoma cells belonging to different breast carcinoma subtypes. Materials and methods. In order to reach this aim, parental and invasive (INV) MDA-MB-231 (triple-negative), T47D (hormone receptor-positive), and Au565 (Her2-positive) breast carcinoma cells were used and their molecular phenotypes were compared using a proteomic approach. Results. Independently from breast cancer subtypes, INV cells have demonstrated fibroblast-like morphology accompanied by enhancement of invasive and migratory capacities, increased expression of cancer stem cell markers, and delayed tumor growth in in vivo animal models. However, the global proteomic analysis has highlighted that INV cells were different in protein expressions from the parental cells, and Her2-positive Au565-INV cells showed the most pronounced molecular differences compared to the triple-negative MDA-MB-231-INV and hormone receptor-positive T47D-INV cells. Although Au565-INV breast carcinoma cells possessed the highest number of deregulated proteins, they had the lowest overlapping in proteins commonly expressed in MDA-MB-231-INV and T47D-INV cells. Conclusions. We can conclude that hormone receptor-positive cells with increased invasiveness acquire the molecular characteristics of triple-negative breast cancer cells, whereas Her2-positive INV cells specifically changed their own molecular phenotype with very limited partaking in the involved pathways found in the MDA-MB-231-INV and T47D-INV cells. Since hormone receptor-positive invasive cells share their molecular properties with triple-negative breast cancer cells, we assume that these types of metastatic disease can be treated rather equally with an option to add anti-hormonal agents. In contrast, Her2-positive metastasis should be carefully evaluated for more effective therapeutic approaches which are distinct from the triple-negative and hormone-positive metastatic breast cancers.
Keywords: breast cancer, cancer stem cells, invasiveness, migration, metastasis
Published in DiRROS: 11.07.2024; Views: 612; Downloads: 225
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Keywords: temporary tracheostoma, distant metastasis, rectal adenocarcinoma, rak (medicina), traheostoma, zasevki, metastaziranje, žlezni rak
Published in DiRROS: 11.04.2024; Views: 680; Downloads: 339
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