Identification of a characteristic vascular belt zone in human colorectal cancer

Kather, Jakob Nikolas; Zöllner, Frank G.; Schad, Lothar R.; Melchers, Susanne; Sinn, Hans‐Peter; Marx, Alexander; Gaiser, Timo; Weis, Cleo–Aron

doi:10.1371/journal.pone.0171378

Cited by 14 publications

(14 citation statements)

References 43 publications

(47 reference statements)

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“…On histological sections, we manually identified areas homogenously occupied by tumor cells or immune cells (in the tumor or around the tumor). The fraction of Ki67-positive cells (active caspase 3-positive cells, respectively) was quantified in these regions of interest (ROI) per slide using a digital pathology approach analogous to our previously published approaches (29,30). Definiens Tissue Studio (Definiens) was used for semiautomatic tissue segmentation and automatic cell segmentation.…”

Section: Histological Assessmentmentioning

confidence: 99%

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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Despite the fact that the local immunological microenvironment shapes the prognosis of colorectal cancer, immunotherapy has shown no benefit for the vast majority of colorectal cancer patients. A better understanding of the complex immunological interplay within the microenvironment is required. In this study, we utilized wet lab migration experiments and quantitative histological data of human colorectal cancer tissue samples (n ¼ 20) including tumor cells, lymphocytes, stroma, and necrosis to generate a multiagent spatial model. The resulting data accurately reflected a wide range of situations of successful and failed immune surveillance. Validation of simulated tissue outcomes on an independent set of human colorectal cancer specimens (n ¼ 37) revealed the model recapitulated the spatial layout typically found in human tumors. Stroma slowed down tumor growth in a lymphocyte-deprived environment but promoted immune escape in a lymphocyteenriched environment. A subgroup of tumors with less stroma and high numbers of immune cells showed high rates of tumor control. These findings were validated using data from colorectal cancer patients (n ¼ 261). Low-density stroma and high lymphocyte levels showed increased overall survival (hazard ratio 0.322, P ¼ 0.0219) as compared with high stroma and high lymphocyte levels. To guide immunotherapy in colorectal cancer, simulation of immunotherapy in preestablished tumors showed that a complex landscape with optimal stroma permeabilization and immune cell activation is able to markedly increase therapy response in silico. These results can help guide the rational design of complex therapeutic interventions, which target the colorectal cancer microenvironment.

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Section: Histological Assessmentmentioning

confidence: 99%

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

et al. 2017

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“…The coupling of dissemination and growth advantage is partly supported by the evidence that seeding cells more likely come from the tumor invasive front, where blood vessels are enriched (Kather et al, 2017).…”

Section: Methodsmentioning

confidence: 99%

“… Seeding proportional to fitness. If λ 0 is the birth rate of type-0 cells and λ 1 the birth rate of type-1 cells, The coupling of dissemination and growth advantage is partly supported by the evidence that seeding cells more likely come from the tumor invasive front, where blood vessels are enriched (Kather et al, 2017). Seeding uniformly over all living cells in the tumor.…”

Section: Methodsmentioning

confidence: 99%

Elements and Evolutionary Determinants of Genomic Divergence Between Paired Primary and Metastatic Tumors

Sun

Νικολακόπουλος

2020

Preprint

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Can metastatic-primary (M-P) genomic divergence measured from next generation sequencing reveal the natural history of metastatic dissemination? This remains an open question of utmost importance in facilitating a deeper understanding of metastatic progression, and thereby, improving its prevention. Here, we utilize mathematical and computational modeling to tackle this question as well as to provide a framework that illuminates the fundamental elements and evolutionary determinants of M-P divergence. Our framework facilitates the integration of sequencing detectability of somatic variants, and hence, paves the way towards bridging the measurable between-tumor heterogeneity with analytical modeling and interpretability. We show that the number of somatic variants of the metastatic seeding cell that are experimentally undetectable in the primary tumor, can be characterized as the path of the phylogenetic tree from the last appearing variant of the seeding cell back to the most recent detectable variant. We find that the expected length of this path is principally determined by the decay in detectability of the variants along the seeding cell's lineage; and thus, exhibits a significant dependence on the underlying tumor growth dynamics. A striking implication of this fact, is that dissemination from an advanced detectable subclone of the primary tumor can lead to an abrupt drop in the expected measurable M-P divergence, thereby breaking the previously assumed monotonic relation between seeding time and M-P divergence. This is emphatically verified by our single cell-based spatial tumor growth simulation, where we find that M-P divergence exhibits a non-monotonic relationship with seeding time when the primary tumor grows under branched and linear evolution. On the other hand, a monotonic relationship holds when we condition on the dynamics of progressive diversification, or by restricting the seeding cells to always originate from undetectable sub-clones. Our results highlight the fact that a precise understanding of tumor growth dynamics is the sine qua non for exploiting M-P divergence to reconstruct the chronology of metastatic dissemination. The quantitative models presented here enable further careful evaluation of M-P divergence in association with crucial evolutionary and sequencing parameters

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“…By referring to previous studies that described the active proliferation and angiogenesis in tumor border, the outer one‐third of the tumor area was assigned as periphery and the other area as the center 12, 13. After drawing the ROI covering the entire tumor areas, the radiologist drew another ROI that passed through two‐thirds of the tumor radius.…”

Section: Methodsmentioning

confidence: 99%

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

et al. 2018

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Tumor heterogeneity is an important concept when assessing intratumoral variety in vascular phenotypes and responses to antiangiogenic treatment. This study explored spatiotemporal heterogeneity of vascular alterations in C6 glioma mice during tumor growth and antiangiogenic treatment on serial MR examinations (days 0, 4, and 7 from initiation of vehicle or multireceptor tyrosine kinase inhibitor administration). Transvascular permeability (TP) was quantified on dynamic‐contrast‐enhanced MRI (DCE‐MRI) using extravascular extracellular agent (Gd‐DOTA); blood volume (BV) was estimated using intravascular T2 agent (SPION). With regard to region‐dependent variability in vascular phenotypes, the control group demonstrated higher TP in the tumor center than in the periphery, and greater BV in the tumor periphery than in the center. This distribution pattern became more apparent with tumor growth. Antiangiogenic treatment effect was regionally heterogeneous: in the tumor center, treatment significantly suppressed the increase in TP and decrease in BV (ie, typical temporal change in the control group); in the tumor periphery, treatment‐induced vascular alterations were insignificant and BV remained high. On histopathological examination, the control group showed greater CD31, VEGFR2, Ki67, and NG2 expression in the tumor periphery than in the center. After treatment, CD31 and Ki67 expression was significantly suppressed only in the tumor center, whereas VEGFR2 and α‐caspase 3 expression was decreased and NG2 expression was increased in the entire tumor. These results demonstrate that MRI can reliably depict spatial heterogeneity in tumor vascular phenotypes and antiangiogenic treatment effects. Preserved angiogenic activity (high BV on MRI and high CD31) and proliferation (high Ki67) in the tumor periphery after treatment may provide insights into the mechanism of tumor resistance to antiangiogenic treatment.

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Identification of a characteristic vascular belt zone in human colorectal cancer

Cited by 14 publications

References 43 publications

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

In Silico Modeling of Immunotherapy and Stroma-Targeting Therapies in Human Colorectal Cancer

Elements and Evolutionary Determinants of Genomic Divergence Between Paired Primary and Metastatic Tumors

Spatiotemporal heterogeneity of tumor vasculature during tumor growth and antiangiogenic treatment: MRI assessment using permeability and blood volume parameters

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