Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity

Nicolini, Andrea; Rossi, Giuseppe; Carpi, Angelo

doi:10.1016/j.semcancer.2020.03.009

Cited by 17 publications

(19 citation statements)

References 204 publications

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“…Cells proliferate rapidly in 2D culture, whereas cells grow more slowly in 3D culture [7]. Slow cycling cancer cells, dormant cancer cells at the G0 phase, and cancer stem cells (CSCs, also called cancer-initiating cells (CICs) or tumor-initiating cells (TICs)) can cause low chemosensitivity, drug resistance, and relapse [8][9][10][11]. These slow and dormant cells are reconstructed in 3D tumoroids, which are accessible by researchers.…”

Section: Introductionmentioning

confidence: 99%

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Sogawa

Eguchi

Namba

et al. 2021

Cells

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Researchers have developed several three-dimensional (3D) culture systems, including spheroids, organoids, and tumoroids with increased properties of cancer stem cells (CSCs), also called cancer-initiating cells (CICs). Drug resistance is a crucial issue involving recurrence in cancer patients. Many studies on anti-cancer drugs have been reported using 2D culture systems, whereas 3D cultured tumoroids have many advantages for assessing drug sensitivity and resistance. Here, we aimed to investigate whether Cisplatin (a DNA crosslinker), Imatinib (a multiple tyrosine kinase inhibitor), and 5-Fluorouracil (5-FU: an antimetabolite) alter the tumoroid growth of metastatic colorectal cancer (mCRC). Gene expression signatures of highly metastatic aggregative CRC (LuM1 cells) vs. low-metastatic, non-aggregative CRC (Colon26 and NM11 cells) were analyzed using microarray. To establish a 3D culture-based multiplexing reporter assay system, LuM1 was stably transfected with the Mmp9 promoter-driven ZsGreen fluorescence reporter gene, which was designated as LuM1/m9 cells and cultured in NanoCulture Plate®, a gel-free 3D culture device. LuM1 cells highly expressed mRNA encoding ABCG2 (a drug resistance pump, i.e., CSC/CIC marker), other CSC/CIC markers (DLL1, EpCAM, podoplanin, STAT3/5), pluripotent stem cell markers (Sox4/7, N-myc, GATA3, Nanog), and metastatic markers (MMPs, Integrins, EGFR), compared to the other two cell types. Hoechst efflux stem cell-like side population was increased in LuM1 (7.8%) compared with Colon26 (2.9%), both of which were markedly reduced by verapamil treatment, an ABCG2 inhibitor. Smaller cell aggregates of LuM1 were more sensitive to Cisplatin (at 10 μM), whereas larger tumoroids with increased ABCG2 expression were insensitive. Notably, Cisplatin (2 μM) and Imatinib (10 μM) at low concentrations significantly promoted tumoroid formation (cell aggregation) and increased Mmp9 promoter activity in mCRC LuM1/m9, while not cytotoxic to them. On the other hand, 5-FU significantly inhibited tumoroid growth, although not completely. Thus, drug resistance in cancer with increased stem cell properties was modeled using the gel-free 3D cultured tumoroid system. The tumoroid culture is useful and easily accessible for the assessment of drug sensitivity and resistance.

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Section: Introductionmentioning

confidence: 99%

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Sogawa

Eguchi

Namba

et al. 2021

Cells

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“…[41][42][43] TGF-β1 can act as a metastatic driver, inducer of EMT transition and impair anti-tumorigenic response. [44][45][46] Thus, our results where increased serum TGF-β1 at 3 months of treatment predicts 6-months MRD status suggest that targeting and/or using TGF-β1 to monitor MCL patients is an interesting prognostic tool. Furthermore, we show that the velocity of change (δ C4 ) of BTK was associated with disease progression.…”

Section: Velocity Profile (δ C4 ) Circumvents Heterogeneity In Protei...mentioning

confidence: 66%

Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

et al. 2021

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Background: The possibility to monitor patient's serum proteome during treatment can provide deepened understanding of the biology associated with response to specific drugs. Non-invasive serum sampling provides an opportunity for sustainable repetitive sampling of patients, which allows for more frequent evaluation of the biological response and enhanced flexibility in treatment selection in contrast to tissue biopsies. Aim: To pin-point biologically relevant changes in pre-and on-treatment serum proteome samples in relapsed mantle cell lymphoma (MCL) patients, leading to insight into mechanisms behind response to treatment in sub-groups of patients. Methods: Pre-and on-treatment serum samples from relapsed MCL patients treated with a triple combination therapy of rituximab, ibrutinib and lenalidomide were available for the study, together with detailed clinicopathological information. A microarray technology targeting 158 serum proteins using 371 antibody-fragments was used to compare the serum proteome at the two time-points. Results: Proteins modulated by the treatment were shown to be associated to a MCL sub-group with ATM/TP53 alterations, which emphasizes the importance of treatment stratification. Absolute values of serum protein levels in on-treatment samples were highly variable and showed no correlation to outcome. To circumvent the challenge of variability in absolute serum protein levels, the velocity of change of individual serum proteins was used to identify proteins associated with clinical response. Increased values of TGF-β1, CD40 and complement component 4 comparing pre-and on-treatment samples were associated with remaining minimal residual disease (MRD) and increased BTK was associated with short progression-free survival (PFS). Conclusion: We show that the genetic sub-type of MCL affects the biological response to treatment in serum and that the change in defined serum proteins reveals the biology associated with clinical response.

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“…Уже положено начало исследованиям, направленным на разработку схем для предотвращения активации и пролиферации ДОК, в особенности у больных с высоким риском рецидива, а также у пациентов с полным ответом на лечение. Предварительные клинические и лабораторные данные свидетельствуют об эффективности этой стратегии при раке желудка и некоторых эндокринозависимых опухолях [19].…”

Section: оригинальные статьиunclassified

Detection of Disseminated Tumor Cells in the Bone Marrow of Patients With Non-Small Cell Lung Cancer

Chulkova

Тупицын

Джуманазаров

et al. 2020

Rossijskij bioterapevtičeskij žurnal

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Существуют многочисленные подтверждения того, что при ряде опухолей диссеминированные опухолевые клетки (ДОК) в костном мозге (КМ)-предшественники последующих отдаленных метастазов. Детекция ДОК при немелкоклеточном раке легкого (НМРЛ) позволит получить важную информацию об особенностях метастазирования и оценить возможности выявления новых мишеней для лекарственной терапии НМРЛ. Цель исследования-оценить возможность детекции ДОК в КМ у больных НМРЛ, а также проанализировать частоту поражения и взаимосвязь с клинико-морфологическими параметрами опухоли.

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Minimal residual disease in advanced or metastatic solid cancers: The G0-G1 state and immunotherapy are key to unwinding cancer complexity

Cited by 17 publications

References 204 publications

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Gel-Free 3D Tumoroids with Stem Cell Properties Modeling Drug Resistance to Cisplatin and Imatinib in Metastatic Colorectal Cancer

Serum proteome modulations upon treatment provides biological insight on response to treatment in relapsed mantle cell lymphoma

Detection of Disseminated Tumor Cells in the Bone Marrow of Patients With Non-Small Cell Lung Cancer

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