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肿瘤学转化研究杂志

体积 6, 问题 3 (2020)

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Tumor stem cells. Bone marrow involvement in melanoma

Chulkova Svetlana Vasilievna1,2

Most of the cancers are still incurable human diseases. All malignant tumors are a heterogeneous population of cells with different biological properties. There are two dominant concepts to explain tumor heterogeneity: the theory of tumor stem cells (TSCs), also called the hierarchical model and the stochastic model. TSCs constitute only a small percentage (0.05-1%) of tumor cells within a tumor mass containing heterogeneous population of tumor cells within the tumor microenvironment. TSCs are closely related to pathological features which result in worse clinical prognosis. TSCs are distinguished by the pronounced expression of anti-apoptotic proteins and the high activity of chemoresistance mediators – ABC-1,2,5, desregulation of signaling pathways Notch, Hedgehog, Wnt. TSCs harbour endogenous resistance mechanisms against radiation and chemotherapy which gives TSCs a survival advantage over differentiated counterparts. The currently known 40 TSC surface markers can express on the hESCs, adult stem cells, and normal tissue cells. Of the 40 TSC markers, approximately 83% (33 out of 40 TSC markers) are rarely expressed on normal tissue cells. 9 of these are already approved as drug target molecules by FDA. A minor TSC subset with maximum resistance to conventional anticancer therapies plays a special role in metastasis. According to the literature, melanoma TSCs are characterized by expression of antigens such as CD44, CD271, and CD133. CD133 is the most frequently studied TSC surface marker in various cancers. In our study we identified TSCs among melanoma DTCs by CD133 expression. 47 bone marrow samples of patients with melanoma were analyzed before treatment by flow cytometry. Among them, stage IV was established in 42.6% of cases. The immunophenotype of the cells was characterized based on the expression of the following antigens: Syto41, CD45, HMB-45, CD133. Evaluation of the expression of antigens was performed within the nucleated cells of Syto41+. Among the evaluated bone marrow samples, the presence of Syto41+CD45-HMB-45+ cells was found in 57.4% of cases. Only in one case, the presence of Syto41+CD45- HMB-45+CD133+ cells was established. The percentage of this subpopulation in this sample was 1.28. It should be mentioned in most cases, patients had an advanced stage of melanoma. This may confirm that CSC marker-negative or marker-positive cancer cells could initiate tumor formation. As demonstrated in our study, flow cytometry with a specific antibody HMB-45 in combination with CD45 is a useful technique to assess BM involvement in melanoma. BM involvement was found in 57.4% of skin melanoma cases. In 28.6% of cases I stage disease was established, which confirms the aggressiveness of skin melanoma even in localized disease. BM as a niche for micrometastasis plays a key role in hematogeneous dissemination. The detection of early dissemination of the tumor process may be a step towards individualization of treatment in this category of patients. At the same time, the identification of cells disseminated in the bone marrow with subsequent testing for the presence of TSCs antigens opens up prospects for the development of methods for influencing melanoma on the TSCs. It is nown that diversity of TSCs may be generated by distinct stemness or reprogramming signalling activations, resulting in divergent expression patterns or TSC markers. Recent findings demonstrates that the TSCs can be newly generated from the differentiated non-TSCs by reprogramming mechanism: even TSCs with different characteristics could emerge. TSCs not only serve as the origin of tumor formation but also drive heterogeneity of cell composition inside the tumor and TSCs themselves. In our study the findings of CD57 and CD133 expression are evidence of TSCs heterogeneity and the complex hierarchical relations between the primary tumor and the dissiminated TCs.

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LIMD2: A novel therapeutic target for metastatic papillary thyroid carcinoma

Rodrigo Pinheiro Araldi

Although the papillary thyroid cancer (PTC) has a good prognosis, the metastatic disease negatively impacts the survival rate. Recent data have been postulated
that the cellular reprograming verified during the metastasis can lead to cancer-stem cells (CSCs) formation, which are related to the therapy failure. In this sense,
we identified that the LIMD2 gene is differentially expressed in PTC and, overexpressed in lymph node metastasis of patients carrying the BRAF V600E mutation,
suggesting that this gene can be involved in CSC formation and, therefore, in therapeutic resistance. In order to investigate this hypothesis, we promoted the
LIMD2 knockout in two cell lines from PTC (BCPAP – BRAF V600E and TPC1 – RET/ PTC) using the CRISPR/Cas9 system. Following validate the LIMD2
editing by TIDE and immunoassays, we analysed the expression CSC-related hallmarkers (SOX-2, OCT-3/4, NANOG, ALDH1A1 and CD44) using proteome
profiler array, flow cytometry and High-Content Screening, the expression levels of thyroid-specific genes (FOXE1, NKX2, PAX8, TG and TPO) by qRT-PCR and
multidrug resistance protein (MRP1) by Western blot. Results showed that the LIMD2 knockout promoted the down regulation of all CSC-related hallmarks, as well
as MRP1 especially in BCPAP edit cells, suggesting that LIMD2 can be associated to the drug efflux. However, we observed an up regulation in the expression
levels of all thyroidspecific genes in BCPAP edit cells, suggesting that LIMD2 is related to the CSC formation in PTC. We also analysed the LIMD2 involvement
in drug resistance mechanisms. For this, we treated both parental and edit cells with acid hydrolysis extract of Agave sisalana (AHEAS), which cytotoxic activity
was previously demonstrated. Results showed that the LIMD2 knockout increased the number of apoptotic/necrotic cells in both edit cell lines. Altogether, these
data strongly suggest that LIMD2 expression can contribute with therapy failure by increasing the MRP1 expression through CSC formation dependent manner.

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Anti-inflammatory drug resistance in breast and colon cancer stem cells: Preclinical leads

Nitin TELANG

Breast and colon cancer together represent major organ site cancers in women. Current treatment options include pathway selective targeted therapy in these cancer subtypes. Additionally, anti-inflammatory drugs have documentedpreclinical and clinical efficacy. Long-term use of these therapeutic options are frequently associated with systemic toxicity, acquired tumor resistance and emergence of drug resistant cancer stem cells. Relatively non-toxic natural products may offer testable alternatives against therapy resistant cancer subtypes. Recent experimental approaches utilize clinically relevant models for breast and colon cancer where gain of expression of human epidermal growth factor receptor-2 (HER-2) oncogene in breast or loss of expression of adenomatous polyposis coli (Apc) tumor suppressor gene in colon represent primary genetic defects and drive carcinogenic process,. Cellular resistance to the non-steroidal anti-inflammatory drug Sulindac selects and enriches drug resistant cancer stem cells. Natural products inhibit the growth of cancer stem cells via downregulated expression of stem cell specific cellular and molecular markers. Collectively, this evidence validates a mechanistic experimental approach to evaluate and prioritize efficacious natural products as agents that target cancer stem cell population. This presentation will provide an overview of clinically relevant rationale for preclinical approaches, published evidence for development of reliable models for breast and colon cancer stem cells, potential clinically translatable mechanistic leads for natural products as testable alternatives for therapy resistant cancer, and future prospects focused on extension of present approaches that are appropriate for patient derived cancer tissues. Collectively, these aspects provide evidence for potential clinical translatability of preclinical data.

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miRNA based advanced differentiation therapy

Maria Salazar Roa

Cancer is a disease of the genome. For a long time, it has been established that cancer mutations are determinant to induce tumor genesis, but recent evidences also point to epigenetic alterations as direct causes of cancer. It is now widely accepted that epigenetic changes are key in the reprogramming of stem and somatic cells into cancer stem cells (CSCs), which constitute the only subset of cancer cells truly immortal and capable of supporting cancer progression. Recent evidences from our group have demonstrated how miRNAs act as potent drivers from pluripotency to expanded differentiation potential, while they block reprogramming from somatic to stem cells. Mechanistically, we have described that these effects are mediated by direct repression of de novo DNA methyltransferases (Dnmt3a and Dnmt3b), leading to a resetting of the epigenetic memory. Given that experimental induction of pluripotency and tumor genesis entail obvious similar pathways, here we speculate that epigenetic changes induced by such miRNAs might unlock the cellular differentiation programs that are normally inactivated in cancer stem cells and at the same time, block the reprogramming from somatic to cancer stem cells, therefore dropping the CSC population in the tumor. Our hypothesis, if confirmed, would shed light on the differentiation-based antitumoral therapy and present those microRNAs as a promising tool for directly confronting the tumormaintaining and regeneration capability of cancer cells.

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SHIKONIN ENHANCES THE ANTITUMOR EFFECTS OF CABAZITAXEL IN PROSTATE CANCER STEM CELLS

Lili Wang, Birgit Stadlbauer and Heike Pohla

Cancer stem cells (CSCs) are a small population among cancer cells, defined as capable of self-renewal, and driving tumor growth, metastasis, and therapeutic
relapse. The development of therapeutic strategies to target CSCs is of great importance to prevent tumor metastasis and relapse. In the last decade, traditional
Chinese medicines (TCM) have been increasingly used as an additional treatment strategy following surgery, chemotherapy, or radiation therapy for cancer
patients worldwide, and accumulating evidences have been shown that some of these substances have significant effects also on CSCs. In our studies the
effect of shikonin on prostate CSCs was analysed. Sphere formation assay was used to generate prostate CSCs. Celltiter blue assay and Celltiter 96 aqueous
one solution proliferation assay were used to evaluate the viability and proliferation. To measure migration and invasion the scratch wound healing assay and
transwell assays were applied. Typical CSC markers were analysed by flow cytometry and quantitative RT-PCR. Furthermore, to characterize the apoptotic
process reactive oxygen species (ROS) and mitochondrial membrane potential were determined. Shikonin inhibits the viability and proliferation of prostate CSCs
in a dose-dependent manner and enhances the effect of cabazitaxel, which is a secondline chemotherapeutic drug in advanced prostate cancer concerning
viability, proliferation, apoptosis, migration, and invasion. Shikonin induces CSC apoptosis through inducing ROS generation, and disrupting the mitochondrial
membrane potential. Furthermore, shikonin suppresses the expression of ALDH3A1 and ABCG2 in prostate CSCs, two markers related to drug-resistance. In
conclusion, shikonin enhances the cytotoxic activity of cabazitaxel in prostate CSCs. Further studies must show to what extent shikonin is also able to abolish
the resistance of tumor cells to cabazitaxel.

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13th International Conference on CANCER STEM CELLS AND ONCOLOGY RESEARCH

Allied Academies hosted the joint event of “13th International Conference on CANCER STEM CELLS AND ONCOLOGY RESEARCH & 3rd Global Expo on CANCER AND ONCOLOGY” on July 30, 2020 as a Webinar with the theme “Hope against Hype - Cancer Stem cells & Oncology Research”. Benevolent response and active participation was received from the Editorial Board Members of supporting International Journals as well as from the leading academic scientists, researchers, research scholars, students and leaders from the field of Cancer & Oncology who made this event successful. The conference was marked by the attendance of young and brilliant researchers, business delegates and talented student communities representing more than 18 countries, who have driven this event into the path of success. The conference highlighted through various sessions on current research.

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