International Journal of Molecular Sciences

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24 pages, 3811 KiB

Open AccessArticle

Comparative Analysis of Primary Ovarian Cancer Cells and Established Cell Lines as a New Tool for Studies on Ovarian Cancer Cell Complexity

by Agnieszka Szyposzynska, Aleksandra Bielawska-Pohl, Maria Paprocka, Julia Bar, Marek Murawski and Aleksandra Klimczak

Int. J. Mol. Sci. 2024, 25(10), 5384; https://doi.org/10.3390/ijms25105384 - 15 May 2024

Viewed by 215

Abstract

Primary cancer cells reflect the genetic background and phenotype of a tumor. Immortalized cells with higher proliferation activity have an advantage over primary cells. The aim of the study was to immortalize the primary ovarian cancer (OvCa) cells using the plasmid-carrying human telomerase [...] Read more.

Primary cancer cells reflect the genetic background and phenotype of a tumor. Immortalized cells with higher proliferation activity have an advantage over primary cells. The aim of the study was to immortalize the primary ovarian cancer (OvCa) cells using the plasmid-carrying human telomerase reverse transcriptase (hTERT) gene and compare their phenotype and biological activity with the primary cells. The primary OvCa3 A and OvCa7 A cells were isolated from the ascitic fluid of two high-grade serous ovarian cancer patients and were characterized using immunocytochemical methods, flow cytometry, real-time RT-PCR, Western blot, metabolic activity, and migratory potential. Both immortalized ovarian cancer cell lines mirrored the phenotype of primary cancer cells, albeit with modifications. The OvCa3 A hTERT cells kept the mesenchymal stem cell phenotype of CD73/CD90/CD105-positivity and were CD133-negative, whereas the cell population of OvCa7 A hTERT lost CD73 expression, but almost 90% of cells expressed the CD133 characteristic for the CSCs phenotype. Immortalized OvCa cells differed in gene expression level with respect to Sox2 and Oct4, which was associated with stemness properties. The OvCa7 A hTERT cells showed higher metabolic and migratory activity and ALDH1 expression than the corresponding primary OvCa cells. Both primary and immortalized cell lines were able to form spheroids. The newly established unique immortalized cell line OvCa7 A hTERT, with the characteristic of a serous ovarian cancer malignancy feature, and with the accumulation of the p53, Pax8, and overexpression of the CD133 and CD44 molecules, may be a useful tool for research on therapeutic approaches, especially those targeting CSCs in ovarian cancer and in preclinical 2D and 3D models. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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15 pages, 8938 KiB

Open AccessArticle

Microbiome Dysbiosis Is Associated with Castration Resistance and Cancer Stemness in Metastatic Prostate Cancer

by Matthew Uzelac, Ruomin Xin and Weg M. Ongkeko

Int. J. Mol. Sci. 2024, 25(6), 3291; https://doi.org/10.3390/ijms25063291 - 14 Mar 2024

Viewed by 633

Abstract

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration resistance often develops during the course of treatment, but its pathogenesis is poorly understood. This study explores [...] Read more.

Prostate cancer is the second leading cause of death in males in America, with advanced prostate cancers exhibiting a 5-year survival rate of only 32%. Castration resistance often develops during the course of treatment, but its pathogenesis is poorly understood. This study explores the human microbiome for its implications in castration resistance and metastasis in prostate cancer. RNA sequencing data were downloaded for the bone and soft tissue biopsies of patients with metastatic castration-resistant prostate cancer. These included both metastatic and adjacent normal biopsies. These sequences were mapped to bacterial sequences, yielding species-level counts. A vast majority of species were found to be significantly underabundant in the CRPC samples. Of these, numerous were found to correlate with the expression of known markers of castration resistance, including AR, PI3K, and AKT. Castration resistance-associated signaling pathways were also enriched with these species, including PI3K-AKT signaling and endocrine resistance. For their implications in cancer aggression and metastasis, cancer stem cell markers were further explored for a relation to these species. EGFR and SLC3A2 were widely downregulated, with a greater abundance of most species. Our results suggest that the microbiome is heavily associated with castration resistance and stemness in prostate cancer. By considering the microbiome’s importance in these factors, we may better understand the highly aggressive and highly invasive nature of castration-resistant prostate cancer, allowing for the needed improvements in the treatment of this disease. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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19 pages, 7142 KiB

Open AccessArticle

Oncogenic Impact of TONSL, a Homologous Recombination Repair Protein at the Replication Fork, in Cancer Stem Cells

by Hani Lee, Sojung Ha, SeokGyeong Choi, Soomin Do, Sukjoon Yoon, Yong Kee Kim and Woo-Young Kim

Int. J. Mol. Sci. 2023, 24(11), 9530; https://doi.org/10.3390/ijms24119530 - 31 May 2023

Cited by 1 | Viewed by 1705

Abstract

We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer [...] Read more.

We investigated the role of TONSL, a mediator of homologous recombination repair (HRR), in stalled replication fork double-strand breaks (DSBs) in cancer. Publicly available clinical data (tumors from the ovary, breast, stomach and lung) were analyzed through KM Plotter, cBioPortal and Qomics. Cancer stem cell (CSC)-enriched cultures and bulk/general mixed cell cultures (BCCs) with RNAi were employed to determine the effect of TONSL loss in cancer cell lines from the ovary, breast, stomach, lung, colon and brain. Limited dilution assays and ALDH assays were used to quantify the loss of CSCs. Western blotting and cell-based homologous recombination assays were used to identify DNA damage derived from TONSL loss. TONSL was expressed at higher levels in cancer tissues than in normal tissues, and higher expression was an unfavorable prognostic marker for lung, stomach, breast and ovarian cancers. Higher expression of TONSL is partly associated with the coamplification of TONSL and MYC, suggesting its oncogenic role. The suppression of TONSL using RNAi revealed that it is required in the survival of CSCs in cancer cells, while BCCs could frequently survive without TONSL. TONSL dependency occurs through accumulated DNA damage-induced senescence and apoptosis in TONSL-suppressed CSCs. The expression of several other major mediators of HRR was also associated with worse prognosis, whereas the expression of error-prone nonhomologous end joining molecules was associated with better survival in lung adenocarcinoma. Collectively, these results suggest that TONSL-mediated HRR at the replication fork is critical for CSC survival; targeting TONSL may lead to the effective eradication of CSCs. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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11 pages, 4272 KiB

Open AccessArticle

Deep Learning of Phase-Contrast Images of Cancer Stem Cells Using a Selected Dataset of High Accuracy Value Using Conditional Generative Adversarial Networks

by Zaijun Zhang, Hiroaki Ishihata, Ryuto Maruyama, Tomonari Kasai, Hiroyuki Kameda and Tomoyasu Sugiyama

Int. J. Mol. Sci. 2023, 24(6), 5323; https://doi.org/10.3390/ijms24065323 - 10 Mar 2023

Cited by 2 | Viewed by 2346

Abstract

Artificial intelligence (AI) technology for image recognition has the potential to identify cancer stem cells (CSCs) in cultures and tissues. CSCs play an important role in the development and relapse of tumors. Although the characteristics of CSCs have been extensively studied, their morphological [...] Read more.

Artificial intelligence (AI) technology for image recognition has the potential to identify cancer stem cells (CSCs) in cultures and tissues. CSCs play an important role in the development and relapse of tumors. Although the characteristics of CSCs have been extensively studied, their morphological features remain elusive. The attempt to obtain an AI model identifying CSCs in culture showed the importance of images from spatially and temporally grown cultures of CSCs for deep learning to improve accuracy, but was insufficient. This study aimed to identify a process that is significantly efficient in increasing the accuracy values of the AI model output for predicting CSCs from phase-contrast images. An AI model of conditional generative adversarial network (CGAN) image translation for CSC identification predicted CSCs with various accuracy levels, and convolutional neural network classification of CSC phase-contrast images showed variation in the images. The accuracy of the AI model of CGAN image translation was increased by the AI model built by deep learning of selected CSC images with high accuracy previously calculated by another AI model. The workflow of building an AI model based on CGAN image translation could be useful for the AI prediction of CSCs. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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Review

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27 pages, 1579 KiB

Open AccessReview

The Impact of Cancer Stem Cells in Colorectal Cancer

by Petru Radu, Mihai Zurzu, Anca Tigora, Vlad Paic, Mircea Bratucu, Dragos Garofil, Valeriu Surlin, Alexandru Claudiu Munteanu, Ionut Simion Coman, Florian Popa, Victor Strambu and Sandu Ramboiu

Int. J. Mol. Sci. 2024, 25(8), 4140; https://doi.org/10.3390/ijms25084140 - 9 Apr 2024

Viewed by 669

Abstract

Despite incessant research, colorectal cancer (CRC) is still one of the most common causes of fatality in both men and women worldwide. Over time, advancements in medical treatments have notably enhanced the survival rates of patients with colorectal cancer. Managing metastatic CRC involves [...] Read more.

Despite incessant research, colorectal cancer (CRC) is still one of the most common causes of fatality in both men and women worldwide. Over time, advancements in medical treatments have notably enhanced the survival rates of patients with colorectal cancer. Managing metastatic CRC involves a complex tradeoff between the potential benefits and adverse effects of treatment, considering factors like disease progression, treatment toxicity, drug resistance, and the overall impact on the patient’s quality of life. An increasing body of evidence highlights the significance of the cancer stem cell (CSC) concept, proposing that CSCs occupy a central role in triggering cancer. CSCs have been a focal point of extensive research in a variety of cancer types, including CRC. Colorectal cancer stem cells (CCSCs) play a crucial role in tumor initiation, metastasis, and therapy resistance, making them potential treatment targets. Various methods exist for isolating CCSCs, and understanding the mechanisms of drug resistance associated with them is crucial. This paper offers an overview of the current body of research pertaining to the comprehension of CSCs in colorectal cancer. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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14 pages, 863 KiB

Open AccessReview

Stearoyl-CoA Desaturase 1 as a Therapeutic Biomarker: Focusing on Cancer Stem Cells

by Jin-Young Min and Do-Hee Kim

Int. J. Mol. Sci. 2023, 24(10), 8951; https://doi.org/10.3390/ijms24108951 - 18 May 2023

Cited by 4 | Viewed by 1719

Abstract

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this [...] Read more.

The dysregulation of lipid metabolism and alterations in the ratio of monounsaturated fatty acids (MUFAs) to saturated fatty acids (SFAs) have been implicated in cancer progression and stemness. Stearoyl-CoA desaturase 1 (SCD1), an enzyme involved in lipid desaturation, is crucial in regulating this ratio and has been identified as an important regulator of cancer cell survival and progression. SCD1 converts SFAs into MUFAs and is important for maintaining membrane fluidity, cellular signaling, and gene expression. Many malignancies, including cancer stem cells, have been reported to exhibit high expression of SCD1. Therefore, targeting SCD1 may provide a novel therapeutic strategy for cancer treatment. In addition, the involvement of SCD1 in cancer stem cells has been observed in various types of cancer. Some natural products have the potential to inhibit SCD1 expression/activity, thereby suppressing cancer cell survival and self-renewal activity. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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21 pages, 955 KiB

Open AccessReview

Cell Therapy as Target Therapy against Colon Cancer Stem Cells

by Elsa N. Garza Treviño, Adriana G. Quiroz Reyes, Juan Antonio Rojas Murillo, David A de la Garza Kalife, Paulina Delgado Gonzalez, Jose F. Islas, Ana Esther Estrada Rodriguez and Carlos A. Gonzalez Villarreal

Int. J. Mol. Sci. 2023, 24(9), 8163; https://doi.org/10.3390/ijms24098163 - 3 May 2023

Cited by 2 | Viewed by 2766

Abstract

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting [...] Read more.

Cancer stem cells (CSCs) are a small subpopulation of cells within tumors with properties, such as self-renewal, differentiation, and tumorigenicity. CSCs have been proposed as a plausible therapeutic target as they are responsible for tumor recurrence, metastasis, and conventional therapy resistance. Selectively targeting CSCs is a promising strategy to eliminate the propagation of tumor cells and impair overall tumor development. Recent research shows that several immune cells play a crucial role in regulating tumor cell proliferation by regulating different CSC maintenance or proliferation pathways. There have been great advances in cellular immunotherapy using T cells, natural killer (NK) cells, macrophages, or stem cells for the selective targeting of tumor cells or CSCs in colorectal cancer (CRC). This review summarizes the CRC molecular profiles that may benefit from said therapy and the main vehicles used in cell therapy against CSCs. We also discuss the challenges, limitations, and advantages of combining conventional and/or current targeted treatments in the late stages of CRC. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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27 pages, 1429 KiB

Open AccessReview

Bromodomain (BrD) Family Members as Regulators of Cancer Stemness—A Comprehensive Review

by Patrycja Czerwinska and Andrzej Adam Mackiewicz

Int. J. Mol. Sci. 2023, 24(2), 995; https://doi.org/10.3390/ijms24020995 - 4 Jan 2023

Cited by 2 | Viewed by 2437

Abstract

Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal [...] Read more.

Epigenetic mechanisms involving DNA methylation and chromatin modifications have emerged as critical facilitators of cancer heterogeneity, substantially affecting cancer development and progression, modulating cell phenotypes, and enhancing or inhibiting cancer cell malignant properties. Not surprisingly, considering the importance of epigenetic regulators in normal stem cell maintenance, many chromatin-related proteins are essential to maintaining the cancer stem cell (CSC)-like state. With increased tumor-initiating capacities and self-renewal potential, CSCs promote tumor growth, provide therapy resistance, spread tumors, and facilitate tumor relapse after treatment. In this review, we characterized the epigenetic mechanisms that regulate the acquisition and maintenance of cancer stemness concerning selected epigenetic factors belonging to the Bromodomain (BrD) family of proteins. An increasing number of BrD proteins reinforce cancer stemness, supporting the maintenance of the cancer stem cell population in vitro and in vivo via the utilization of distinct mechanisms. As bromodomain possesses high druggable potential, specific BrD proteins might become novel therapeutic targets in cancers exhibiting de-differentiated tumor characteristics. Full article

(This article belongs to the Special Issue New Advance on Cancer Stem Cells)

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