Mechanistic Insights into Colorectal Cancer Phenomics from Fundamental and Organotypic Model Studies

Campbell, Frederick Charles; Loughrey, Maurice B.; McClements, Jane; Deevi, Ravi Kiran; Javadi, Arman; Rainey, Lisa

doi:10.1016/j.ajpath.2018.05.021

Cited by 8 publications

(11 citation statements)

References 99 publications

(221 reference statements)

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“…In addition, RNA interference of RhoA or treatment with a ROCK inhibitor eliminated the inverted polarity [21,23,24]. The similarity between inverted features of polarity and the MPC phenotype has been suggested [26]. On the other hand, the model MPC system used in this study is different from MDCK cells in some ways.…”

Section: Discussionmentioning

confidence: 99%

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Onuma

Sato

Okuyama

et al. 2021

The Journal of Pathology

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Micropapillary carcinoma (MPC) is a morphologically distinctive form of carcinoma, composed of small nests of cancer cells surrounded by lacunar spaces. Invasive MPC is associated with poor prognosis. The nests of tumor cells in MPC reportedly exhibit reverse polarity, although the molecular mechanisms underlying MPC patterns are poorly understood. Using the cancer tissue‐originated spheroid (CTOS) method, we previously reported polarity switching in colorectal cancer (CRC). When cultured in suspension, the apical membrane promptly switches from the outside surface of the CTOSs to the surface of the lumen inside the CTOSs under extracellular matrix (ECM)‐embedded conditions, and vice versa. Here, we investigated two CTOS lines from CRC patient tumors with MPC lesions. Xenograft tumors from the CTOSs exhibited the MPC phenotype. The MPC‐CTOSs did not switch polarity in vitro. Time‐course analysis of polarity switching using real‐time imaging of the apical membrane revealed that local switching was continually propagated in non‐MPC‐CTOSs, while MPC‐CTOSs were unable to complete the process. Integrin β4 translocated to the outer membrane when embedded in ECM in both MPC and non‐MPC‐CTOSs. Protein levels, as well as the active form of RhoA, were higher in MPC‐CTOSs. The suppression of RhoA activity by GAP overexpression enabled MPC‐CTOSs to complete polarity switching both in vitro and in vivo, while overexpression of active RhoA did not affect polarity switching in non‐MPC‐CTOSs. Pretreatment with a ROCK inhibitor enabled MPC‐CTOSs to complete polarity switching both in vitro and in vivo, although delayed treatment after becoming embedded in ECM failed to do so. Thus, the inability to switch polarity might be a cause of MPC, in which the aberrant activation of RhoA plays a critical role. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Section: Discussionmentioning

confidence: 99%

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Onuma

Sato

Okuyama

et al. 2021

The Journal of Pathology

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“…To survive in such conditions, cells must respond either by inhibiting pro‐apoptotic signaling or by activating anti‐apoptotic mechanisms (5,6). It is likely that, in addition to anoikis resistance, other aberrations, such as suppression of apical polarity signaling (23), contribute to formation of the putative AR structures. Supporting the concept of multicellular groups without ECM contact indicating anoikis resistance, we have recently shown that transfection of Caco‐2 cells with mutated KRAS or BRAF gene induces anoikis resistance (12) and, simultaneously, changes 3D growth from simple unilayered cysts to either focal piling of the cells reminiscent of MIP structures or solid growth reminiscent of solid structures, respectively (12).…”

Section: Discussionmentioning

confidence: 99%

Putative anoikis‐resistant subpopulations in colorectal carcinoma: a marker of adverse prognosis

Patankar

Mattila

Väyrynen

et al. 2020

APMIS

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Patankar M, Mattila T, V€ ayrynen JP, Klintrup K, M€ akel€ a J, Tuomisto A, Nieminen P, M€ akinen MJ, Karttunen TJ. Putative anoikis-resistant subpopulations in colorectal carcinoma: a marker of adverse prognosis. APMIS 2020; 128: 390-400.Anoikis is a form of apoptosis induced when a cell loses contact with the extracellular matrix (ECM). Anoikis resistance is essential for metastasis formation, yet only detectable by in vitro experiments. We present a method for quantitation of putative anoikis-resistant (AR) subpopulations in colorectal carcinoma (CRC) and evaluate their prognostic significance. We studied 137 CRC cases and identified cell subpopulations with and without stromal or extracellular matrix (ECM) contact with hematoxylin-and-eosin-stained sections and immunohistochemistry for laminin and type IV collagen. Suprabasal cells of micropapillary structures and inner cells of cribriform and solid structures lacked both stromal contact and contact with ECM proteins. Apoptosis rate (M30) was lower in these subpopulations than in the other carcinoma cells, consistent with putative AR subpopulation. We determined the areal density of these subpopulations (number/mm 2 tumor tissue), and their high areal density independently indicates low cancer-specific survival. In conclusion, we show evidence that subpopulations of carcinoma cells in micropapillary, cribriform, and solid structures are resistant to anoikis as shown by lack of ECM contact and low apoptosis rate. Abundance of these subpopulations is a new independent indicator of poor prognosis in CRC, consistent with the importance of anoikis resistance in the formation of metastasis.

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“…Classically, CRC diagnosis and prognostic stratification are based on histopathologic assessment of cell or nuclear pleomorphism, aberrant mitotic figures, altered glandular architecture, and other phenomic abnormalities [94]. From this standpoint, complexity may involve oncogenic perturbation of spatiotemporal signaling, leading to disruption at multiple levels of tissue organization.…”

Section: Consensus Molecular Subtypes (Cms Classification)mentioning

confidence: 99%

Back to the Colorectal Cancer Consensus Molecular Subtype Future

Menter

Davis

Broom

et al. 2019

Curr Gastroenterol Rep

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Purpose of Review-This review seeks to provide an informed prospective on the advances in molecular profiling and analysis of colorectal cancer (CRC). The goal is to provide a historical context and current summary on how advances in gene and protein sequencing technology along with computer capabilities led to our current bioinformatic advances in the field. Recent Findings-An explosion of knowledge has occurred regarding genetic, epigenetic, and biochemical alterations associated with the evolution of colorectal cancer. This has led to the realization that CRC is a heterogeneous disease with molecular alterations often dictating natural history, response to treatment, and outcome. The consensus molecular subtypes (CMS) classification classifies CRC into four molecular subtypes with distinct biological characteristics, which may form the basis for clinical stratification and subtype-based targeted intervention. Summary-This review summarizes new developments of a field moving "Back to the Future." CRC molecular subtyping will better identify key subtype specific therapeutic targets and responses to therapy.

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Mechanistic Insights into Colorectal Cancer Phenomics from Fundamental and Organotypic Model Studies

Cited by 8 publications

References 99 publications

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Aberrant activation of Rho/ROCK signaling in impaired polarity switching of colorectal micropapillary carcinoma

Putative anoikis‐resistant subpopulations in colorectal carcinoma: a marker of adverse prognosis

Back to the Colorectal Cancer Consensus Molecular Subtype Future

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