Intravasation as a Key Step in Cancer Metastasis

Zavyalova, М. V.; Denisov, Evgeny V.; Таширева, Л. А.; Savelieva, O.E.; Кайгородова, Е. В.; Krakhmal, N. V.; Перельмутер, В. М.

doi:10.1134/s0006297919070071

Cited by 75 publications

(39 citation statements)

References 76 publications

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“…It is conceivable that the intravasation process is accessible for cells with various initial phenotypes. This suggestion was confirmed by data regarding the presence of intravasation mechanisms of tumor cells deprived of invasive characteristics [21,25].…”

Section: Discussionsupporting

confidence: 54%

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Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer

Savelieva

Таширева

Кайгородова

et al. 2020

IJMS

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The presence of stem and epithelial–mesenchymal-transition (EMT) features in circulating tumor cells (CTCs) determines their invasiveness, adaptability to the microenvironment, and resistance to proapoptotic signals and chemotherapy. It also allows them to fulfil the role of metastatic “seeds”. We evaluated the heterogeneity of stem CTCs by their CD44, ALDH1, and CD133 expression depending on N-cadherin expression in breast-cancer patients. A total of 38 female patients were selected for this study. CTC phenotypes were determined by flow cytometry before any type of treatment. Multiplex immunofluorescence was used for the evaluation of tumor-cell heterogeneity in primary lesions. In patients who had CD44-CD24- CTCs, a subset of cells with the expression of other stem-cell markers (CD133 and ALDH1) were detected. Expression of CD133 and/or ALDH1 may be associated with expression of N-cadherin: all populations of N-cadherin+ CTCs demonstrate stem features; in the absence of N-cadherin expression, true nonstem (CD44-CD24-CD133-ALDH1-) cells are found. The heterogeneity of stem marker expression in CTCs was observed regardless of N-cadherin expression. In our study, stromal cell-derived factor-1 (SDF-1) receptor expression in CTCs did not depend on stemlike traits, but was instead associated with N-cadherin expression. Subpopulations of tumor cells, detected both in tumors and blood, were identified. Breast cancer was characterized by pronounced interpersonal and intrapersonal heterogeneity of CTCs by the presence and combination of various stem features and N-cadherin expression. To complete the characterization of stemlike features of CTCs, we suggest the simultaneous use of the three stem markers.

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Section: Discussionsupporting

confidence: 54%

“…Not all tumor cells have intravasation capability. This capability was shown in different model systems [21].…”

Section: Discussionmentioning

confidence: 83%

Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer

Savelieva

Таширева

Кайгородова

et al. 2020

IJMS

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“…We also showed that CTCs are highly heterogeneous population in breast cancer and have similar phenotypes to STCs: various combinations of the stem and EMT features or the absence of these marks (32). The similarity of STC and CTC phenotypes may indicate the high ability of STCs to intravasation (33).…”

Section: Discussionmentioning

confidence: 58%

Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis

et al. 2020

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Introduction: The identification of tumor cells that can be potential metastatic seeds would reach two key aims-prognosis of metastasis risk and appointment of the optimal adjuvant therapy to prevent metastatic disease. Single tumor cells (STCs) located out of multicellular structures can most likely demonstrate features that are needed to initiate metastasis.Methods: One-hundred-and-thirty-five patients with invasive breast carcinoma of no special type have been enrolled. Molecular subtypes of breast cancer were categorized according to St. Gallen recommendations. Hematoxylin and eosin staining was used to identify STCs with epithelial-like morphology (eSTCs) in breast tumors. Immunofluorescence staining was applied to evaluate stemness and epithelial-mesenchymal transition (EMT) in STCs. The correlation between STCs and recurrence and metastasis-free survival (MFS) was performed using the Kaplan-Meier method and the log-rank test.Results: Distant metastasis was more frequent in eSTC-positive than eSTC-negative patients (28.0% vs. 9.4%, p = 0.007). When tumor types were analyzed separately, distant metastasis tended to be more frequent in eSTC-positive than eSTC-negative patients for HER2-positive cancer [75.0% (3/4) vs. 12.5% (1/8), p = 0.066]. In luminal A [22.7% (5/22) vs. 10.0% (3/30), p = 0.259], luminal B [21.1% (4/19) vs. 6.7% (2/30), p = 0.189], and triple-negative [40.0% (2/5) vs. 11.8% (2/17), p = 0.209] cancers, distance metastasis was not associated with eSTCs. Median MFS was not reached in eSTC-positive and eSTC-negative patients. eSTC-positive patients had a higher risk of breast cancer metastasis [hazard ratio (HR) 3.57, 95% confidence interval (CI): 1.46-8.71; p = 0.001]. When tumor types were analyzed separately, a higher risk of breast cancer metastasis occurred only in HER2-positive patients (HR 8.49, 95% CI: 1.29-55.59; p = 0.016). Immunofluorescence analysis revealed mesenchymal-like STCs (mSTCs) and inter-and intra-tumor heterogeneity in STCs. There were breast tumors with either eSTCs or mSTCs and tumors with Tashireva et al.Single Tumor Cells Are Associated With Metastasis both types of STCs. Both eSTCs and mSTCs were represented by cells with different stem and/or EMT phenotypes.Conclusions: STCs with epithelial-like morphology contribute to breast cancer metastasis and represent an attractive model for studying mechanisms of metastatic seeding. The assessment of STCs in histological sections of breast tumors can be a simple and effective method for the prediction of metastasis risk.

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“…), and appearance phenotypic and structural changes associated with increased cell motility and invasiveness [8,67,68]. Increased invasiveness promotes intravasation of tumor cells and ensures their survival in circulation [5,69]. Furthermore, EMT-induced phenotypic changes are associated with acquired stemness, resistance to therapy, and immunosuppression [70].…”

Section: Phenotypic Heterogeneitymentioning

confidence: 99%

Heterogeneity of Circulating Tumor Cells in Breast Cancer: Identifying Metastatic Seeds

Menyailo

Tretyakova

Denisov

2020

IJMS

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Metastasis being the main cause of breast cancer (BC) mortality represents the complex and multistage process. The entrance of tumor cells into the blood vessels and the appearance of circulating tumor cells (CTCs) seeding and colonizing distant tissues and organs are one of the key stages in the metastatic cascade. Like the primary tumor, CTCs are extremely heterogeneous and presented by clusters and individual cells which consist of phenotypically and genetically distinct subpopulations. However, among this diversity, only a small number of CTCs is able to survive in the bloodstream and to form metastases. The identification of the metastasis-initiating CTCs is believed to be a critical issue in developing therapeutic strategies against metastatic disease. In this review, we summarize the available literature addressing morphological, phenotypic and genetic heterogeneity of CTCs and the molecular makeup of specific subpopulations associated with BC metastasis. Special attention is paid to the need for in vitro and in vivo studies to confirm the tumorigenic and metastatic potential of metastasis-associating CTCs. Finally, we consider treatment approaches that could be effective to eradicate metastatic CTCs and to prevent metastasis. with partial EMT) and high metastatic potential [18,19]. In addition to the EMT features, CTCs can also exhibit stem-like characteristics, particularly self-renewal and multilineage differentiation ability [20].There is still no highly effective therapy for metastatic BC. Therapy targeted directly against CTCs seems to be promising. To date, various molecular markers of CTCs and their therapeutic targets that can be used to prevent cancer progression are known [21]. In addition, different therapeutic approaches for the elimination of CTCs have been proposed; however, none of them has been clinically approved. The reason is that the molecular and biological characteristics of the primary tumor and CTCs are not well understood. In our opinion, the main focus should be on the search for specific populations of CTCs responsible for the development of metastasis and the study of their molecular makeup. These cells could be the primary therapeutic target for preventing metastatic progression [22]. Recent advances in single-cell sequencing allow one to determine the population structure of CTCs and identify metastasis-initiating cells [23][24][25][26], while in vitro and in vivo studies provide data on their proliferative, apoptotic, invasive, and other phenotypes [27].Nowadays, despite a large number of studies on CTC heterogeneity and their metastatic potential, there are still no generally accepted and universal markers of CTCs prone to metastasis. In this review, we systematized the data on metastatic CTCs in terms of their morphological, phenotypic, and genetic heterogeneity in BC, as well as emphasized the importance of studying these cells in vitro and in vivo and developing therapeutic approaches for their elimination to prevent metastasis. CTC Heterogeneity and the Molecular Makeup...

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Intravasation as a Key Step in Cancer Metastasis

Cited by 75 publications

References 76 publications

Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer

Heterogeneity of Stemlike Circulating Tumor Cells in Invasive Breast Cancer

Single Tumor Cells With Epithelial-Like Morphology Are Associated With Breast Cancer Metastasis

Heterogeneity of Circulating Tumor Cells in Breast Cancer: Identifying Metastatic Seeds

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