scholarly journals Rigid tumors contain soft cancer cells

2021 ◽  
Author(s):  
Thomas Fuhs ◽  
Franziska Wetzel ◽  
Anatol Fritsch ◽  
Xinzhi Li ◽  
Roland Stange ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Primary Tumor ◽  
Single Cells ◽  
Tissue Level ◽  
Surrounding Tissue ◽  
Primary Tumors ◽  
Tumor Mass ◽  
Cell Clusters ◽  
Cell Shapes

Abstract Palpation, as already mentioned in the ancient Egyptian medical text Ebers Papyrus, utilizes that solid tumors are stiffer than the surrounding tissue. However, cancer cell lines tend to soften, which may intuitively foster invasion by enhancing the ability of cancer cells to squeeze through dense tissue. This paradox raises questions besides the oxymoron itself: Does softness emerge from adaptation to the external microenvironment? Or are soft cells already present inside a rigid primary tumor mass to support cancer cell unjamming? We investigate primary tumor explants from patients with breast and cervix carcinomas on multiple length scales from the tissue level down to single cells. We find that primary tumors are highly heterogeneous in their mechanical properties. From the tissue level this heterogeneity persists down to the scale of individual cells in cancer cell clusters, resulting in a broad distribution of cell rigidities with a higher fraction of softer, more squeezable cells. Plus, squeezed cell shapes correlate with cancer cell motility. Mechanical modelling based on patient data reveals that a tumor mass as a whole is able to maintain a rigid, solid behavior even when it contains a significant fraction of very soft cells. Cell softening induced cancer cell unjamming generates heterogeneous cancer cell clusters with a solid backbone of rigid cells surrounded by soft motile cells.

scholarly journals A mathematical framework for modelling the metastatic spread of cancer

2018 ◽  
Author(s):  
Linnéa C Franßen ◽  
Tommaso Lorenzi ◽  
Andrew EF Burgess ◽  
Mark AJ Chaplain
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Complex Disease ◽  
Single Cells ◽  
The Body ◽  
Metastatic Spread ◽  
Surrounding Tissue ◽  
Mathematical Framework ◽  
Cell Clusters ◽  
Modelling Framework

AbstractCancer is a complex disease that starts with mutations of key genes in one cell or a small group of cells at a primary site in the body. If these cancer cells continue to grow successfully and, at some later stage, invade the surrounding tissue and acquire a vascular network (tumour-induced angiogenesis), they can spread to distant secondary sites in the body. This process, known as metastatic spread, is responsible for around 90% of deaths from cancer and is one of the so-called hallmarks of cancer.To shed light on the metastatic process, we present a mathematical modelling framework that captures for the first time the interconnected processes of invasion and metastatic spread of individual cancer cells in a spatially explicit manner — a multi-grid, hybrid, individual-based approach. This framework accounts for the spatio-temporal evolution of mesenchymal- and epithelial-like cancer cells, as well as MT1-MMP and MMP-2 dynamics, and interactions with the extracellular matrix.Using computational simulations, we demonstrate that our model captures all the key steps of the invasion-metastasis cascade, i.e. invasion by both heterogeneous cancer cell clusters and by single mesenchymal-like cancer cells; intravasation of these clusters and single cells both via active mechanisms mediated by matrix degrading enzymes (MDEs) and via passive shedding; circulation of cancer cell clusters and single cancer cells in the vasculature with the associated risk of cell death and disaggregation of clusters; extravasation of clusters and single cells; and metastatic growth at distant secondary sites in the body. By faithfully reproducing experimental results, our simulations support the evidence-based hypothesis that the membrane-bound MT1-MMP is the main driver of invasive spread rather than diffusible MDEs like MMP-2.

scholarly journals Hydrodynamic stress stimulates growth of cell clusters via the ANXA1/PI3K/AKT axis in colorectal cancer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Takeshi Hagihara ◽  
Jumpei Kondo ◽  
Hiroko Endo ◽  
Masayuki Ohue ◽  
Yoshiharu Sakai ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Cancer Cell ◽  
Single Cells ◽  
Membrane Damage ◽  
Metastatic Potential ◽  
Blood Stream ◽  
Cancer Tissue ◽  
Hydrodynamic Stress ◽  
Cell Clusters

AbstractCancer cells are exposed to various stresses in vivo, including hydrodynamic stress (HDS). HDS on cancer cells in the blood stream can influence the metastatic potential. Recent studies revealed that circulating tumor cell clusters are more responsible for metastasis than circulating single cells. Nevertheless, most studies on HDS are based on single cells prepared from established cancer cell lines. Here, we used cancer tissue-originated spheroids (CTOS) as a patient-derived, 3D organoid model to investigate the effect of HDS on cancer cell clusters. We found that HDS induced the growth of cancer cell clusters in a population of colorectal CTOSs. Microarray analyses revealed that the multifunctional protein, Annexin 1 (ANXA1), was upregulated upon HDS exposure. Chemically-induced membrane damage also triggered the expression of ANXA1. A knockdown of ANXA1 revealed that ANXA1 regulated HDS-stimulated growth in colorectal CTOSs. Mechanistically, activating the PI3K/AKT pathway downstream of ANXA1 contributed to the phenotype. These findings demonstrate that HDS induces the growth of cancer cell clusters via ANXA1/PI3K/AKT axis, which helps to elucidate the pro-metastatic feature of circulating cancer cell clusters.

scholarly journals Breast Cancer Cell Re-Dissemination from Lung Metastases—A Mechanism for Enhancing Metastatic Burden

2021 ◽  
Vol 10 (11) ◽  
pp. 2340
Author(s):  
Lucia Borriello ◽  
John Condeelis ◽  
David Entenberg ◽  
Maja H. Oktay
Keyword(s):  
Breast Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Disease ◽  
Breast Cancer Cells ◽  
Lung Metastases ◽  
Primary Tumors ◽  
Metastatic Burden ◽  
First Time ◽  
Do So

Although metastatic disease is the primary cause of mortality in cancer patients, the mechanisms leading to overwhelming metastatic burden are still incompletely understood. Metastases are the endpoint of a series of multi-step events involving cancer cell intravasation, dissemination to distant organs, and outgrowth to metastatic colonies. Here we show, for the first-time, that breast cancer cells do not solely disseminate to distant organs from primary tumors and metastatic nodules in the lymph nodes, but also do so from lung metastases. Thus, our findings indicate that metastatic dissemination could continue even after the removal of the primary tumor. Provided that the re-disseminated cancer cells initiate growth upon arrival to distant sites, cancer cell re-dissemination from metastatic foci could be one of the crucial mechanisms leading to overt metastases and patient demise. Therefore, the development of new therapeutic strategies to block cancer cell re-dissemination would be crucial to improving survival of patients with metastatic disease.

scholarly journals An Ex-Vivo Culture System of Ovarian Cancer Faithfully Recapitulating the Pathological Features of Primary Tumors

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 644 ◽  
Author(s):  
Ghani ◽  
Dendo ◽  
Watanabe ◽  
Yamada ◽  
Yoshimatsu ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Epithelial Ovarian Cancer ◽  
Cancer Cells ◽  
Cell Lines ◽  
Cancer Cell ◽  
Xenograft Model ◽  
Culture Method ◽  
Cancer Cell Lines ◽  
Ovarian Cancer Cells ◽  
Primary Tumors

The success rate of establishing human cancer cell lines is not satisfactory and the established cell lines often do not preserve the molecular and histological features of the original tissues. In this study, we developed a novel culture method which can support proliferation of almost all primary epithelial ovarian cancer cells, as well as primary normal human oviductal epithelial cells. Cancer cells from fresh or frozen specimens were enriched by the anti-EpCAM antibody-conjugated magnetic beads, plated on Matrigel-coated plate and cultivated under the optimized culture conditions. Seventeen newly established ovarian cancer cell lines, which included all four major histotypes of ovarian cancer, were confirmed to express histotype-specific markers in vitro. Some of the cell lines from all the four histotypes, except mucinous type, generated tumors in immune-deficient mice and the xenograft tumor tissues recapitulated the corresponding original tissues faithfully. Furthermore, with poorly tumorigenic cell lines including mucinous type, we developed a novel xenograft model which could reconstruct the original tissue architecture through forced expression of a set of oncogenes followed by its silencing. With combination of the novel culture method and cell-derived xenograft system, virtually every epithelial ovarian cancer can be reconstituted in mice in a timely fashion.

scholarly journals Host deficiency in ephrin-A1 inhibits breast cancer metastasis

F1000Research ◽  
2020 ◽  
Vol 9 ◽  
pp. 217 ◽  
Author(s):  
Eileen Shiuan ◽  
Ashwin Inala ◽  
Shan Wang ◽  
Wenqiang Song ◽  
Victoria Youngblood ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Growth ◽  
Cancer Cell ◽  
Lung Metastasis ◽  
Primary Tumor ◽  
Tumor Recurrence ◽  
Cancer Metastasis ◽  
Primary Tumor Growth ◽  
Primary Tumors ◽  
4T1 Cells

Background: The conventional dogma of treating cancer by focusing on the elimination of tumor cells has been recently refined to include consideration of the tumor microenvironment, which includes host stromal cells. Ephrin-A1, a cell surface protein involved in adhesion and migration, has been shown to be tumor suppressive in the context of the cancer cell. However, its role in the host has not been fully investigated. Here, we examine how ephrin-A1 host deficiency affects cancer growth and metastasis in a murine model of breast cancer. Methods: 4T1 cells were orthotopically implanted into the mammary fat pads or injected into the tail veins of ephrin-A1 wild-type (Efna1+/+), heterozygous (Efna1+/-), or knockout (Efna1-/-) mice. Tumor growth, lung metastasis, and tumor recurrence after surgical resection were measured. Flow cytometry and immunohistochemistry (IHC) were used to analyze various cell populations in primary tumors and tumor-bearing lungs. Results: While primary tumor growth did not differ between Efna1+/+, Efna1+/-, and Efna1-/- mice, lung metastasis and primary tumor recurrence were significantly decreased in knockout mice. Efna1-/- mice had reduced lung colonization of 4T1 cells compared to Efna1+/+ littermate controls as early as 24 hours after tail vein injection. Furthermore, established lung lesions in Efna1-/- mice had reduced proliferation compared to those in Efna1+/+ controls. Conclusions: Our studies demonstrate that host deficiency of ephrin-A1 does not impact primary tumor growth but does affect metastasis by providing a less favorable metastatic niche for cancer cell colonization and growth. Elucidating the mechanisms by which host ephrin-A1 impacts cancer relapse and metastasis may shed new light on novel therapeutic strategies.

scholarly journals Comprehensive transcriptomic analysis of cell lines as models of primary tumor samples across 22 tumor types

2018 ◽  
Author(s):  
K. Yu ◽  
B. Chen ◽  
D. Aran ◽  
J. Charalel ◽  
A. Butte ◽  
...  
Keyword(s):  
Cancer Research ◽  
Cell Line ◽  
Cell Lines ◽  
Cancer Cell ◽  
Primary Tumor ◽  
Cancer Biology ◽  
Cancer Cell Lines ◽  
Primary Tumors ◽  
Tumor Types

AbstractCancer cell lines are commonly used as models for cancer biology. While they are limited in their ability to capture complex interactions between tumors and their surrounding environment, they are a cornerstone of cancer research and many important findings have been discovered utilizing cell line models. Not all cell lines are appropriate models of primary tumors, however, which may contribute to the difficulty in translating in vitro findings to patients. Previous studies have leveraged public datasets to evaluate cell lines as models of primary tumors, but they have been limited in scope to specific tumor types and typically ignore the presence of tumor infiltrating cells in the primary tumor samples. We present here a comprehensive pan-cancer analysis utilizing approximately 9,000 transcriptomic profiles from The Cancer Genome Atlas and the Cancer Cell Line Encyclopedia to evaluate cell lines as models of primary tumors across 22 different tumor types. After adjusting for tumor purity in the primary tumor samples, we performed correlation analysis and differential gene expression analysis between the primary tumor samples and cell lines. We found that cell-cycle pathways are consistently upregulated in cell lines, while no pathways are consistently upregulated across the primary tumor samples. In a case study, we compared colorectal cancer cell lines with primary tumor samples across the colorectal subtypes and identified three colorectal cell lines that were derived from fibroblasts rather than tumor epithelial cells. Lastly, we propose a new set of cell lines panel, the TCGA-110, which contains the most representative cell lines from 22 different tumor types as a more comprehensive and informative alternative to the NCI-60 panel. Our analysis of the other tumor types are available in our web app (http://comphealth.ucsf.edu/TCGA110) as a resource to the cancer research community, and we hope it will allow researchers to select more appropriate cell line models and increase the translatability of in vitro findings.

scholarly journals A Mesenchymal-like Program of Dormancy controlled by ZFP281 Serves as a Barrier To Metastatic Progression of Early Disseminated Cancer Cells

2021 ◽  
Author(s):  
Julio Aguirre-Ghiso ◽  
Ana Rita Nobre ◽  
Erica Dalla ◽  
Jihong Yang ◽  
Xin Huang ◽  
...  
Keyword(s):  
Single Cell ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Metastatic Progression ◽  
In Vivo Models ◽  
Primary Tumors ◽  
Rate Limiting Step ◽  
Metastasis Models

Abstract Increasing evidence shows that cancer cells can disseminate from early-evolved primary lesions much earlier than the classical metastasis models predicted. It is thought that a state of early disseminated cancer cell (early DCC) dormancy can precede genetic maturation of DCCs and metastasis initiation. Here we reveal at single cell resolution a previously unrecognized role of mesenchymal- and pluripotency-like programs in coordinating early cancer cell spread and a long-lived dormancy program in early DCCs. Using in vitro and in vivo models of invasion and metastasis, single cell RNA sequencing and human sample analysis, we provide unprecedented insight into how early DCC heterogeneity and plasticity control the timing of reactivation. We identify in early lesions and early DCCs the transcription factor ZFP281 as an inducer of mesenchymal- and primed pluripotency-like programs, which is absent in advanced primary tumors and overt metastasis. ZFP281 not only controls the early spread of cancer cells but also locks early DCCs in a prolonged dormancy state by preventing the acquisition of an epithelial-like proliferative program and consequent metastasis outgrowth. Thus, ZFP281-driven dormancy of early DCCs may be a rate-limiting step in metastatic progression functioning as a first barrier that DCCs must overcome to then undergo genetic maturation.

Feasibility of multiple immunoexpression assay for immune tumor micrornvironment (I-TME) on matched metastatic and primary renal cell carcinoma (RCC) for patient prognostication and predictiveness to immunotherapy (preliminary analyses of the Meet URO 18 study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16545-e16545
Author(s):  
Matteo Brunelli ◽  
Sara Elena Rebuzzi ◽  
Valerio Gaetano Vellone ◽  
Marta Sbaraglia ◽  
Gabriele Gaggero ◽  
...  
Keyword(s):  
Nk Cells ◽  
Primary Tumor ◽  
Progression Free Survival ◽  
Tissue Expression ◽  
Tissue Level ◽  
Antibody Testing ◽  
Tissue Samples ◽  
Primary Tumors ◽  
Cd8 Cells ◽  
Primary Renal Cell Carcinoma

e16545 Background: The Meet-URO 18 study is ongoing to assess the prognostic role of I-TME in advanced RCC patients treated with ≥second line nivolumab divided into two cohorts according to clinical benefit [progression-free survival ≥ 12 and ≤ 3 months]. We primarily assessed the feasibility of multiple antibody testing related to I-TME on matched metastases and primary tumor. Methods: Immunohistochemical analyses were used for the TME assessment of T-lineage (CD3, CD4, CD8), FOXP-3, granulocytes (CD15), macrophage-lineage (CD68), natural killer (NK)-cells (CD56), tumor cells (TCs) (CD56), B-lineage (CD20) and phosphorylated mTOR (phmTOR). TCs were quantitatively assessed for CD15, CD56 and phmTOR positivity. For T-, B- and CD68 cells within TC nests, the number of immunoreactive cells were counted with a microscopic field of x200 (0.933 mm2). Results: Overall, 42 tumor tissue samples (primary tumors, metastases) were available and for 17 patients both metastatic and primary tumor tissues were assessable for matched analyses. Among these patients, 12 had clear cell, 1 papillary and 4 mucinous tubular and spindle cell histotype according to WHO 2016 classification. Intratumoral T/CD8 cells ranged from 32 to >400 spots (mean 240; >400 in 7 samples) and intratumoral T/CD4 cells from 4 to >400 spots (mean 168; >400 in 5 samples). Nine samples showed absence of phmTOR expression, while 8 ranged from 10% to 90% of positive TCs. We did not observe countable NK-cells, whereas CD56 was visible in 5 samples (mean 55% of positive TCs). Intratumoral CD68 cells ranged from 34 to >400 spots (mean 175, >400 in 3 patients). Agreement of CD15 method of reporting granulocytic presence was high, thus only CD15 neoplastic expression was reported and ranged from 12% to 55% (mean 30%) in 15 patients. TME multiple analysis resulted equally clustered in 8 patients (<20% variability of single immuno-test) whereas the remaining 9 patients showed significant differences as percentage of immuno-tissue expression in at least one of the 5 immuno-indicators (T/CD8-CD4, C15, CD68, CD56, phmTOR). The remaining 8 samples of patients without matched analyses were used to test the feasibility of multiple analyses; among all antibodies exclusion of the CD20 and FOXP-3 final evaluation was needed, due to technical standardization. According to the 5 immuno-indicators, double-triple positive or penta-positive TME indicators may be identified and graded. Conclusions: Providing multiple immunoexpression platforms on a single specimen may be used as routine workflow. Profiling I-TME, especially CD56, CD15 on TCs and CD68 cells and phmTOR, deserves investigation with extensive control groups. A validation cohort will be tested at tissue level and in correlation with peripheral blood markers.

scholarly journals Inhibition of Ovarian Cancer Cell Spheroid Formation by Synthetic Peptides Derived from Nectin-4

2020 ◽  
Vol 21 (13) ◽  
pp. 4637
Author(s):  
Kristin L.M. Boylan ◽  
Rory D. Manion ◽  
Heena Shah ◽  
Keith M. Skubitz ◽  
Amy P. N. Skubitz
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Synthetic Peptides ◽  
Ovarian Cancer Cell ◽  
Single Cells ◽  
Ovarian Cancer Cells ◽  
Dependent Manner ◽  
Spheroid Formation ◽  
Multicellular Spheroids

The formation of 3D multicellular spheroids in the ascites fluid of ovarian cancer patients is an understudied component of the disease progression. Spheroids are less sensitive to chemotherapy, in part due to the protection afforded by their structure, but also due to their slower proliferation rate. Previous studies suggest that the cell adhesion molecule Nectin-4 plays a key role in the formation of ovarian cancer spheroids. In this study, we further examined the role of Nectin-4 at early time points in spheroid formation using real-time digital photography. Human NIH:OVCAR5 ovarian cancer cells formed aggregates within 8 h, which further contracted into compact spheroids over 24 h. In contrast, Nectin-4 knockdown cells did not form tightly compacted spheroids. Synthetic peptides derived from Nectin-4 were tested for their ability to alter spheroid formation in two ovarian cancer cell lines. Nectin-4 peptide 10 (N4-P10) had an immediate effect on disrupting ovarian cancer spheroid formation, which continued for over 24 h, while a scrambled version of the peptide had no effect. N4-P10 inhibited spheroid formation in a concentration-dependent manner and was not cytotoxic; suggesting that N4-P10 treatment could maintain the cancer cells as single cells which may be more sensitive to chemotherapy.

scholarly journals Profiling site-specific cell states of Ewing Sarcoma xenografts in zebrafish

2021 ◽  
Author(s):  
Dagan Segal ◽  
Hanieh Mazloom-Farsibaf ◽  
Bo-Jui Chang ◽  
Philippe Roudot ◽  
Mikako Warren ◽  
...  
Keyword(s):  
Cancer Cell ◽  
Ewing Sarcoma ◽  
Metastatic Potential ◽  
Functional Adaptation ◽  
Surrounding Tissue ◽  
Specific Cell ◽  
Learning Approaches ◽  
Fish Embryo ◽  
Cell Shapes ◽  
Specific Tissue

A key challenge in cancer research is to identify functional cell states as they relate to specific tissue microenvironments. In this work, we present a quantitative high-resolution imaging assay of cancer cell morphology in zebrafish xenografts to probe functional adaptation to variable cell extrinsic cues and molecular interventions. We focus on Ewing Sarcoma, a pediatric cancer driven by a single oncogenic fusion protein EWSR1-FLI1, and with little to no additional somatic mutations, making it a prototypical form of cancer whose adaptation is likely driven by acute, non-genomic mechanisms. By applying machine learning approaches to 3D cell shapes, we find systematic shifts in the distribution of cell morphological states between seeding sites in the fish embryo, as well as between cells with differential expression of EWSR1-FLI1 in an environmentally sensitive fashion. We propose a model where Ewing Sarcoma cancer cell plasticity is sensitive both to expression fluctuation of EWSR1-FLI1 and signals from the surrounding tissue microenvironment, with either or both factors possibly contributing to metastatic potential.

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