Transcriptome profile of the early stages of breast cancer tumoral spheroids

Pacheco-Marín, Rosario; Meléndez-Zajgla, Jorge; Castillo-Rojas, Gonzalo; Mandujano-Tinoco, Edna Ayerim; García-Venzor, Alfredo; Uribe‐Carvajal, Salvador; Cabrera‐Orefice, Alfredo; González-Torres, Carolina; Gaytán-Cervantes, Javier; Mitre-Aguilar, Irma B.; Maldonado, Vilma

doi:10.1038/srep23373

Cited by 21 publications

(21 citation statements)

References 51 publications

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“…Although the literature on this topic is extensive [ 1 – 7 ], many aspects of tumor cell biology and survival in the context of a 3-dimensional (3D) environment remain poorly understood. For decades the Multicellular Tumor Spheroid (MCTS) model has been used to study clinically relevant aspects of tumor biology, including hypoxia [ 8 ], protein expression patterns within tumors [ 9 – 11 ], and responses to therapeutics [ 9 , 10 , 12 – 23 ]. However, relatively few experiments have attempted to use MCTS to further our understanding of tumor cell adaptations within a hypoxic microenvironment.…”

Section: Introductionmentioning

confidence: 99%

“…Spheroids exceeding 400 μm in diameter develop a hypoxic core and activate known survival signaling pathways to maintain cell viability. Tumor cells grown as MCTS, TS, TDTS, and OMS display regional heterogeneity in tumor cell proliferation [ 44 , 46 , 47 ], metabolic activity [ 9 – 11 , 32 , 44 , 48 , 49 ], and DNA damage repair (DDR) signaling [ 9 , 50 – 53 ]. In addition to the influence of the 3D microenvironment, the genetic background of the tumor cells and stromal cell populations also contribute to the specifics of spheroid regionalization [ 39 , 54 – 56 ].…”

Section: Introductionmentioning

confidence: 99%

“…Studies using radiolabeled glucose and mathematical modeling revealed a critical threshold for glucose and oxygen diffusion into the MCTS core, beyond which chronic starvation results in cell death [ 56 , 93 ]. Recent findings detailing protein expression and metabolic adaptations within MCTS resemble metabolic profiles described in vivo [ 9 , 11 , 49 , 54 , 94 , 95 ]. The accumulation of glycogen stores under mild hypoxia and subsequent breakdown of these stores into glucose under severe hypoxia represents one such adaptation [ 49 ].…”

Section: Introductionmentioning

confidence: 99%

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Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids

Riffle

Hegde

2017

J Exp Clin Cancer Res

155

121

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Under hypoxic conditions, tumor cells undergo a series of adaptations that promote evolution of a more aggressive tumor phenotype including the activation of DNA damage repair proteins, altered metabolism, and decreased proliferation. Together these changes mitigate the negative impact of oxygen deprivation and allow preservation of genomic integrity and proliferative capacity, thus contributing to tumor growth and metastasis. As a result the presence of a hypoxic microenvironment is considered a negative clinical feature of many solid tumors. Hypoxic niches in tumors also represent a therapeutically privileged environment in which chemo- and radiation therapy is less effective. Although the negative impact of tumor hypoxia has been well established, the precise effect of oxygen deprivation on tumor cell behavior, and the molecular signals that allow a tumor cell to survive in vivo are poorly understood. Multicellular tumor spheroids (MCTS) have been used as an in vitro model for the avascular tumor niche, capable of more accurately recreating tumor genomic profiles and predicting therapeutic response. However, relatively few studies have used MCTS to study the molecular mechanisms driving tumor cell adaptations within the hypoxic tumor environment. Here we will review what is known about cell proliferation, DNA damage repair, and metabolic pathways as modeled in MCTS in comparison to observations made in solid tumors. A more precise definition of the cell populations present within 3D tumor models in vitro could better inform our understanding of the heterogeneity within tumors as well as provide a more representative platform for the testing of therapeutic strategies.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids

Riffle

Hegde

2017

J Exp Clin Cancer Res

155

121

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“…Coregulation of lncRNAs and neighboring genes is an area of active research in understanding lncRNA functions. For example, 138 coexpressed lncRNA–mRNA pairs were identified from differentially expressed lncRNAs and mRNAs in human glioblastomas [ 74 ] and 63 co-regulated lncRNAs and mRNAs were found in human breast cancer spheroids [ 75 ]. In our study, the overlapping transcripts, HAfT3 and Tex36 (unknown function), and their concurrent increased transcription suggest they may be a linked gene pair for coexpression.…”

Section: Discussionmentioning

confidence: 99%

HAfTs are novel lncRNA transcripts from aflatoxin exposure

et al. 2018

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The transcriptome can reveal insights into precancer biology. We recently conducted RNA-Seq analysis on liver RNA from male rats exposed to the carcinogen, aflatoxin B1 (AFB1), for 90 days prior to liver tumor onset. Among >1,000 differentially expressed transcripts, several novel, unannotated Cufflinks-assembled transcripts, or HAfTs (Hepatic Aflatoxin Transcripts) were found. We hypothesized PCR-cloning and RACE (rapid amplification of cDNA ends) could further HAfT identification. Sanger data was obtained for 6 transcripts by PCR and 16 transcripts by 5’- and 3’-RACE. BLAST alignments showed, with two exceptions, HAfT transcripts were lncRNAs, >200nt without apparent long open reading frames. Six rat HAfT transcripts were classified as ‘novel’ without RefSeq annotation. Sequence alignment and genomic synteny showed each rat lncRNA had a homologous locus in the mouse genome and over half had homologous loci in the human genome, including at least two loci (and possibly three others) that were previously unannotated. While HAfT functions are not yet clear, coregulatory roles may be possible from their adjacent orientation to known coding genes with altered expression that include 8 HAfT-gene pairs. For example, a unique rat HAfT, homologous to Pvt1, was adjacent to known genes controlling cell proliferation. Additionally, PCR and RACE Sanger sequencing showed many alternative splice variants and refinements of exon sequences compared to Cufflinks assembled transcripts and gene prediction algorithms. Presence of multiple splice variants and short tandem repeats found in some HAfTs may be consequential for secondary structure, transcriptional regulation, and function. In summary, we report novel, differentially expressed lncRNAs after exposure to the genotoxicant, AFB1, prior to neoplastic lesions. Complete cloning and sequencing of such transcripts could pave the way for a new set of sensitive and early prediction markers for chemical hepatocarcinogens.

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“…Breast cancer mammospheres exhibit realistic profiles of oncogenes and tumor biomarkers, which could then be used to identify therapeutic gene targets for metastatic breast cancer 43. A recent study by Pacheco-Marin et al44 found that 3D breast cancer mammospheres displayed a “metastatic signature” involving the downregulation of several cell-adhesion molecules (ie, EPCAM, E-cadherin, integrins, etc), suggesting that the tumor cells were more likely to separate, migrate, and metastasize. Another report has shown that mammospheres express biomarkers (eg, vimentin) that are involved in EMT, which is known to promote tumor metastasis 45.…”

Section: Biological Models For Breast Cancer Researchmentioning

confidence: 99%

Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

Sambi¹,

Haq²,

Samuel³

et al. 2017

BCTT

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One of the primary challenges in developing effective therapies for malignant tumors is the specific targeting of a heterogeneous cancer cell population within the tumor. The cancerous tumor is made up of a variety of distinct cells with specialized receptors and proteins that could potentially be viable targets for drugs. In addition, the diverse signals from the local microenvironment may also contribute to the induction of tumor growth and metastasis. Collectively, these factors must be strategically studied and targeted in order to develop an effective treatment protocol. Targeted multimodal approaches need to be strategically studied in order to develop a treatment protocol that is successful in controlling tumor growth and preventing metastatic burden. Breast cancer, in particular, presents a unique problem because of the variety of subtypes of cancer that can arise and the multiple drug targets that could be exploited. For example, the tumor stage and subtypes often dictate the appropriate treatment regimen. Alternate multimodal therapies should consider the importance of time-dependent drug administration, as well as targeting the local and systemic tumor environment. Many reviews and papers have briefly touched on the clinical implications of this cellular heterogeneity; however, there has been very little discussion on the development of study models that reflect this diversity and on multimodal therapies that could target these subpopulations. Here, we summarize the current understanding of the origins of intratumoral heterogeneity in breast cancer subtypes, and its implications for tumor progression, metastatic potential, and treatment regimens. We also discuss the advantages and disadvantages of utilizing specific breast cancer models for research, including in vitro monolayer systems and three-dimensional mammospheres, as well as in vivo murine models that may have the capacity to encompass this heterogeneity. Lastly, we summarize some of the current advancements in the development of multitarget therapeutics that have shown promising results in clinical and preclinical studies when used alone or in combination with traditional regimens of surgery, chemotherapy, and/or radiation.

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Transcriptome profile of the early stages of breast cancer tumoral spheroids

Cited by 21 publications

References 51 publications

Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids

Modeling tumor cell adaptations to hypoxia in multicellular tumor spheroids

HAfTs are novel lncRNA transcripts from aflatoxin exposure

Alternative therapies for metastatic breast cancer: multimodal approach targeting tumor cell heterogeneity

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