Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Stanta, Giorgio; Bonin, Serena

doi:10.3389/fmed.2018.00085

Cited by 196 publications

(164 citation statements)

References 121 publications

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“…31,32 Whereas the effects of telomerase inhibition in tumour cells are expected only after many mitotic cycles, the development of resistance (by several mechanisms) can be a limiting factor for the use of these inhibitors on cancer therapy. 31,32 Whereas the effects of telomerase inhibition in tumour cells are expected only after many mitotic cycles, the development of resistance (by several mechanisms) can be a limiting factor for the use of these inhibitors on cancer therapy.…”

Section: Discussionmentioning

confidence: 99%

“…Heterogeneous cultures reflect the intra-tumour heterogeneity (ITH), what is recognized as a big challenge for treatment of many kinds of cancer, including breast cancer. 31,32 Whereas the effects of telomerase inhibition in tumour cells are expected only after many mitotic cycles, the development of resistance (by several mechanisms) can be a limiting factor for the use of these inhibitors on cancer therapy. Thus, it is important to take these facts into account when considering any anti-telomerase clinical approach.…”

Section: Discussionmentioning

confidence: 99%

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Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Morais

Arcanjo

Lopes

et al. 2019

Cell Biochemistry & Function

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Telomerase is a good target for new anticancer drug development because it is present in over 85% of human tumours. However, despite chronic therapy is a condition for anti-telomerase approach, the effects of long-term treatment with telomerase inhibitors remain not well understood. In this work, it was evaluated the effects of long-term treatment of human MDA-MB-231 breast cancer cells with the telomerase inhibitor MST-312. Cells were treated for 72 hours or 140 days, and it was accessed their viability, proliferation rate, morphology, telomeric DNA content, and resistance mechanism. The drug had a clear short-term effect, including chemosensitizing cells for docetaxel and irinotecan, but the chronic exposition led to selection of long telomeres clones, changing characteristics of original cell line. This effect was confirmed in a clonal culture with homogenous karyotype. MRP-1 expression and alternative lengthening of telomeres (ALT) were discarded as additional mechanisms of resistance. This data suggest that, considering the intra-tumour heterogeneity (ITH), what is already a big challenge for treatment of cancer, chronic exposition to telomerase inhibitors can promote tumour adaptations with potential clinical repercussion, drawing attention to ongoing clinical trials and pointing important considerations most times neglected on studies about use of these inhibitors on cancer therapy.Significance of the study: Antitumour action of telomerase inhibitors is well known, but it depends on a long-term exposition because cells will undergo telomere erosion only after many duplication cycles. Recently, the frustrating results of clinical trials with these inhibitors aroused the interest of the scientific community to understand the mechanisms of resistance to anti-telomerase therapy. In this study, we conducted an 18-week experiment to show that telomerase inhibition can lead to cell adaptations and selection of long-telomeres clones, leading to acquisition of resistance. However, we also showed that this inhibitor can sensitize cells to the chemotherapeutic drugs docetaxel and irinotecan.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Morais

Arcanjo

Lopes

et al. 2019

Cell Biochemistry & Function

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“…To leverage this gland level clonality, we microdissected individual spots (small regions consisting of 2-5 adjacent glands each) from multiple regions of microscope slides (Fig 2a) obtained from 12 human colorectal tumors (Table 1). From each primary tumor, two (one for tumor R) arbitrarily located sections were collected and a median of 13 spots (range: [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] per slide were microdissected. The average minimum distance between neighboring spots was 2.9 mm, with an average pairwise distance of 8.4 mm between dots on the same slide.…”

Section: Saturation Microdissection Of Tumor Slidesmentioning

confidence: 99%

“…However, intratumor heterogeneity (ITH) is common in human tumors and the ancestral information recorded by subclonal mutations can be used to reconstruct their growth [1][2][3] . The interpretation of the ancestral information encoded by ITH is critical because knowledge about tumor initiation and progression informs effective strategies to prevent, detect, and treat human cancers [4][5][6] .…”

Section: Introductionmentioning

confidence: 99%

Minimal Barriers to Invasion During Human Colorectal Tumor Growth

Ryser

Mallo

Hall

et al. 2019

Preprint

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Intra-tumoral heterogeneity (ITH) could represent clonal evolution where subclones with greater fitness confer more malignant phenotypes and invasion constitutes an evolutionary bottleneck. Alternatively, ITH could represent branching evolution with invasion of multiple subclones. The two models respectively predict a hierarchy of subclones arranged by phenotype, or multiple subclones with shared phenotypes. We delineated these modes of invasion by merging ancestral, topographic, and phenotypic information from 12 human colorectal tumors (11 carcinomas, 1 adenoma) obtained through saturation microdissection of 325 small tumor regions. The majority of subclones (29/46, 60%) shared superficial and invasive phenotypes. Of 11 carcinomas, 9 showed evidence of multiclonal invasion, and invasive and metastatic subclones arose early along the ancestral trees. Early multiclonal invasion in the majority of these tumors indicates the expansion of co-evolving subclones with similar malignant potential in absence of late bottlenecks, and suggests that barriers to invasion are minimal during colorectal cancer growth.

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“…And nowadays, tumor microenvironment has arisen more interests which generally means non-cancerous cells present in and around a tumor (Buoncervello et al, 2019;Ferrone and Whiteside, 2007;Zheng and Gao, 2019), and especially, tumor immune microenvironment which focuses on immune cells has become one research hotspot (Bao et al, 2019;Jiang et al, 2019;. On the other hand, intra-tumor heterogeneity denotes that some subpopulations of cancer cells which differ in their genetic patterns, phenotypic characteristics or cell type composition within a given tumor tissue (Cresswell et al, 2016;Stanta and Bonin, 2018;Wright et al, 2017). Each subpopulation of cancer cells would build up a distinct subclone and if get a growth advantage, that subclonal population can expand over time and inhibit proliferation of normal cells (Giessler et al, 2017;Newcomb et al, 1978).…”

Section: Introductionmentioning

confidence: 99%

Single-cell RNA-seq data reveals TNBC tumor heterogeneity through characterizing subclone compositions and proportions

Wang

et al. 2019

Preprint

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Understanding subclonal architecture and their biological functions poses one of the key challenges to deeply portray and investigative the cause of triple-negative breast cancer (TNBC). Here we combine single-cell and bulk sequencing data to analyze tumor heterogeneity through characterizing subclone compositions and proportions. Based on sing-cell RNA-seq data (GSE118389) we identified five distinct cell subpopulations and characterized their biological functions based on their gene markers. It is worth noting that C1 and C2 relate to immune functions, while C5 relates to programmed cell death. Then based on subclonal basis gene expression matrix, we applied CBS deconvolution algorithm on TCGA tissue RNA-seq data, and found that patients with low and high C1 proportions have different immune microenvironment;and high C5 proportions would led to poor survival outcome, p-value and HR [95%CI] for five years overall survival in TCGA dataset were 0.0326 and 1.664 [1.038-2.667], and in GSE96058 dataset were 0.0158 and 2.557 [1.160-5.636]. Collectively, our analysis reveals the both intra-tumor and inter-tumor heterogeneity and their association with subclonal microenvironment in TNBC (subclone compositions and proportions), and uncovers the organic combination of subclones dictating poor outcomes in this disease.

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Overview on Clinical Relevance of Intra-Tumor Heterogeneity

Cited by 196 publications

References 121 publications

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Long‐term in vitro treatment with telomerase inhibitor MST‐312 induces resistance by selecting long telomeres cells

Minimal Barriers to Invasion During Human Colorectal Tumor Growth

Single-cell RNA-seq data reveals TNBC tumor heterogeneity through characterizing subclone compositions and proportions

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