Metastatic dissemination occurs very early in the malignant progression of a cancer but the clinical manifestation of metastases often takes years. In recent decades, 5-year survival of patients with ...many solid cancers has increased due to earlier detection, local disease control and adjuvant therapies. As a consequence, we are confronted with an increase in late relapses as more antiproliferative cancer therapies prolong disease courses, raising questions about how cancer cells survive, evolve or stop growing and finally expand during periods of clinical latency. I argue here that the understanding of early metastasis formation, particularly of the currently invisible phase of metastatic colonization, will be essential for the next stage in adjuvant therapy development that reliably prevents metachronous metastasis.
Cancer is often regarded as a process of asexual evolution driven by genomic and genetic instability. Mutation, selection and adaptation are by convention thought to occur primarily within, and to a ...lesser degree outside, the primary tumour. However, disseminated cancer cells that remain after 'curative' surgery exhibit extreme genomic heterogeneity before the manifestation of metastasis. This heterogeneity is later reduced by selected clonal expansion, suggesting that the disseminated cells had yet to acquire key traits of fully malignant cells. Abrogation of the cells' progression outside the primary tumour implies new challenges and opportunities for diagnosis and adjuvant therapies.
Systemic cancer progression is accounted for in two basic models. The prevailing archetype places the engine of cancer progression within the primary tumour before metastatic dissemination of fully ...malignant cells. The second posits parallel, independent progression of metastases arising from early disseminated tumour cells. This Perspective draws together data from disease courses, tumour growth rates, autopsy studies, clinical trials and molecular genetic analyses of primary and disseminated tumour cells in support of the parallel progression model. Consideration of this model urges review of current diagnostic and therapeutic routines.
Tumor Cell Invasion in Glioblastoma Vollmann-Zwerenz, Arabel; Leidgens, Verena; Feliciello, Giancarlo ...
International journal of molecular sciences,
03/2020, Volume:
21, Issue:
6
Journal Article
Peer reviewed
Open access
Glioblastoma (GBM) is a particularly devastating tumor with a median survival of about 16 months. Recent research has revealed novel insights into the outstanding heterogeneity of this type of brain ...cancer. However, all GBM subtypes share the hallmark feature of aggressive invasion into the surrounding tissue. Invasive glioblastoma cells escape surgery and focal therapies and thus represent a major obstacle for curative therapy. This review aims to provide a comprehensive understanding of glioma invasion mechanisms with respect to tumor-cell-intrinsic properties as well as cues provided by the microenvironment. We discuss genetic programs that may influence the dissemination and plasticity of GBM cells as well as their different invasion patterns. We also review how tumor cells shape their microenvironment and how, vice versa, components of the extracellular matrix and factors from non-neoplastic cells influence tumor cell motility. We further discuss different research platforms for modeling invasion. Finally, we highlight the importance of accounting for the complex interplay between tumor cell invasion and treatment resistance in glioblastoma when considering new therapeutic approaches.
Cancer. The metastasis cascade Klein, Christoph A
Science (American Association for the Advancement of Science),
2008-Sep-26, 20080926, Volume:
321, Issue:
5897
Journal Article
Metastasis is the leading cause of cancer-related deaths; metastatic lesions develop from disseminated cancer cells (DCCs) that can remain dormant. Metastasis-initiating cells are thought to ...originate from a subpopulation present in progressed, invasive tumours. However, DCCs detected in patients before the manifestation of breast-cancer metastasis contain fewer genetic abnormalities than primary tumours or than DCCs from patients with metastases. These findings, and those in pancreatic cancer and melanoma models, indicate that dissemination might occur during the early stages of tumour evolution. However, the mechanisms that might allow early disseminated cancer cells (eDCCs) to complete all steps of metastasis are unknown. Here we show that, in early lesions in mice and before any apparent primary tumour masses are detected, there is a sub-population of Her2
p-p38
p-Atf2
Twist1
E-cad
early cancer cells that is invasive and can spread to target organs. Intra-vital imaging and organoid studies of early lesions showed that Her2
eDCC precursors invaded locally, intravasated and lodged in target organs. Her2
eDCCs activated a Wnt-dependent epithelial-mesenchymal transition (EMT)-like dissemination program but without complete loss of the epithelial phenotype, which was reversed by Her2 or Wnt inhibition. Notably, although the majority of eDCCs were Twist1
E-cad
and dormant, they eventually initiated metastasis. Our work identifies a mechanism for early dissemination in which Her2 aberrantly activates a program similar to mammary ductal branching that generates eDCCs that are capable of forming metastasis after a dormancy phase.
The pathogenesis of glioblastoma (GBM) is characterized by highly invasive behavior allowing dissemination and progression. A conclusive image of the invasive process is not available. The aim of ...this work was to study invasion dynamics in GBM using an innovative in vivo imaging approach. Primary brain tumor initiating cell lines from IDH-wild type GBM stably expressing H2B-Dendra2 were implanted orthotopically in the brains of SCID mice. Using high-resolution time-lapse intravital imaging, tumor cell migration in the tumor core, border and invasive front was recorded. Tumor cell dynamics at different border configurations were analyzed and multivariate linear modelling of tumor cell spreading was performed. We found tumor border configurations, recapitulating human tumor border morphologies. Not only tumor borders but also the tumor core was composed of highly dynamic cells, with no clear correlation to the ability to spread into the brain. Two types of border configurations contributed to tumor cell spreading through distinct invasion patterns: an invasive margin that executes slow but directed invasion, and a diffuse infiltration margin with fast but less directed movement. By providing a more detailed view on glioma invasion patterns, our study may improve accuracy of prognosis and serve as a basis for personalized therapeutic approaches.
Accumulating data suggest that metastatic dissemination often occurs early during tumour formation, but the mechanisms of early metastatic spread have not yet been addressed. Here, by studying ...metastasis in a HER2-driven mouse breast cancer model, we show that progesterone-induced signalling triggers migration of cancer cells from early lesions shortly after HER2 activation, but promotes proliferation in advanced primary tumour cells. The switch from migration to proliferation was regulated by increased HER2 expression and tumour-cell density involving microRNA-mediated progesterone receptor downregulation, and was reversible. Cells from early, low-density lesions displayed more stemness features, migrated more and founded more metastases than cells from dense, advanced tumours. Notably, we found that at least 80% of metastases were derived from early disseminated cancer cells. Karyotypic and phenotypic analysis of human disseminated cancer cells and primary tumours corroborated the relevance of these findings for human metastatic dissemination.
Abstract
Molecular single cell analyses provide insights into physiological and pathological processes. Here, in a stepwise approach, we first evaluate 19 protocols for single cell small RNA ...sequencing on MCF7 cells spiked with 1 pg of 1,006 miRNAs. Second, we analyze MCF7 single cell equivalents of the eight best protocols. Third, we sequence single cells from eight different cell lines and 67 circulating tumor cells (CTCs) from seven SCLC patients. Altogether, we analyze 244 different samples. We observe high reproducibility within protocols and reads covered a broad spectrum of RNAs. For the 67 CTCs, we detect a median of 68 miRNAs, with 10 miRNAs being expressed in 90% of tested cells. Enrichment analysis suggested the lung as the most likely organ of origin and enrichment of cancer-related categories. Even the identification of non-annotated candidate miRNAs was feasible, underlining the potential of single cell small RNA sequencing.
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