Metabolic Escape Routes of Cancer Stem Cells and Therapeutic Opportunities

Although improvement in early diagnosis and treatment ameliorated life expectancy of cancer patients, metastatic disease still lacks effective therapeutic approaches. Resistance to anticancer therapies stems from the refractoriness of a subpopulation of cancer cells—termed cancer stem cells (CSCs)—which is endowed with tumor initiation and metastasis formation potential. CSCs are heterogeneous and diverge by phenotypic, functional and metabolic perspectives. Intrinsic as well as extrinsic stimuli dictated by the tumor microenvironment (TME)have critical roles in determining cell metabolic reprogramming from glycolytic toward an oxidative phenotype and vice versa, allowing cancer cells to thrive in adverse milieus. Crosstalk between cancer cells and the surrounding microenvironment occurs through the interchange of metabolites, miRNAs and exosomes that drive cancer cells metabolic adaptation. Herein, we identify the metabolic nodes of CSCs and discuss the latest advances in targeting metabolic demands of both CSCs and stromal cells with the scope of improving current therapies and preventing cancer progression.

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Role of Organ Specific Cancer Stem Cells in Organ Specific Cancer Progression

Journal of Genes and Cells ◽

10.15562/gnc.74 ◽

2020 ◽

Vol 6 (2) ◽

pp. 21

Author(s):

Muhammad Ali ◽

Fatima Ali ◽

Nadia Wajid

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Cancer Biology ◽

Cancer Therapeutics ◽

Therapeutic Approaches ◽

Specific Cancer ◽

Organ Specific

Since the cancer stem cells (CSC) have been identified in 1997 by Bonnet and Dick, more than 100,000 papers have been published on the CSC. Huge research on cancer stem cells helped the scientists to rethink about the cancer therapeutics as classic way of chemotherapy is ineffective because chemotherapy failed to kill these cells, the only reason of cancer relapse. The cancer theory of stem cells is one of the most trending theory in stem cells and cancer biology focusing on the understanding of biology of cancer cells for an enhanced and improved therapeutic approaches should be applied to cure the cancer. This mini-review is a short overview on the role of organ specific cancer stem cells in the organ specific cancer progression.

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Matrix Stiffness Modulates Metabolic Interaction between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

Metabolites ◽

10.3390/metabo11070432 ◽

2021 ◽

Vol 11 (7) ◽

pp. 432

Author(s):

Iván Ponce ◽

Nelson Garrido ◽

Nicolás Tobar ◽

Francisco Melo ◽

Patricio C. Smith ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Glucose Transporter ◽

Lactate Production ◽

Resonance Energy ◽

Metabolic Reprogramming ◽

Dependent Manner ◽

Functional Link

Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work was to investigate the possible functional link between these two processes. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material, to which matrix molecules were covalently linked. We evaluated metabolite transport in stromal cells using two different FRET (Fluorescence Resonance Energy Transfer) nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response was correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote metabolic reprograming and also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming, and cancer malignancy.

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Hampering Stromal Cells in the Tumor Microenvironment as a Therapeutic Strategy to Destem Cancer Stem Cells

Cancers ◽

10.3390/cancers13133191 ◽

2021 ◽

Vol 13 (13) ◽

pp. 3191

Author(s):

Katherine Po Sin Chung ◽

Rainbow Wing Hei Leung ◽

Terence Kin Wah Lee

Keyword(s):

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Stromal Cells ◽

Current Knowledge ◽

Special Focus ◽

Intrinsic Regulation ◽

Mechanistic Basis ◽

Novel Therapeutic Strategies

Cancer stem cells (CSCs) within the tumor bulk play crucial roles in tumor initiation, recurrence and therapeutic resistance. In addition to intrinsic regulation, a growing body of evidence suggests that the phenotypes of CSCs are also regulated extrinsically by stromal cells in the tumor microenvironment (TME). Here, we discuss the current knowledge of the interplay between stromal cells and cancer cells with a special focus on how stromal cells drive the stemness of cancer cells and immune evasive mechanisms of CSCs. Knowledge gained from the interaction between CSCs and stromal cells will provide a mechanistic basis for the development of novel therapeutic strategies for the treatment of cancers.

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Metabolic cooperation between cancer and non-cancerous stromal cells is pivotal in cancer progression

Tumor Biology ◽

10.1177/1010428318756203 ◽

2018 ◽

Vol 40 (2) ◽

pp. 101042831875620 ◽

Cited By ~ 11

Author(s):

Filipa Lopes-Coelho ◽

Sofia Gouveia-Fernandes ◽

Jacinta Serpa

Keyword(s):

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Inflammatory Cells ◽

Metabolic Adaptation ◽

Metabolic Cooperation ◽

Metabolic Remodeling ◽

Organ Tissue ◽

Cancerous Cells

The way cancer cells adapt to microenvironment is crucial for the success of carcinogenesis, and metabolic fitness is essential for a cancer cell to survive and proliferate in a certain organ/tissue. The metabolic remodeling in a tumor niche is endured not only by cancer cells but also by non-cancerous cells that share the same microenvironment. For this reason, tumor cells and stromal cells constitute a complex network of signal and organic compound transfer that supports cellular viability and proliferation. The intensive dual-address cooperation of all components of a tumor sustains disease progression and metastasis. Herein, we will detail the role of cancer-associated fibroblasts, cancer-associated adipocytes, and inflammatory cells, mainly monocytes/macrophages (tumor-associated macrophages), in the remodeling and metabolic adaptation of tumors.

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miR-216a Acts as a Negative Regulator of Breast Cancer by Modulating Stemness Properties and Tumor Microenvironment

International Journal of Molecular Sciences ◽

10.3390/ijms21072313 ◽

2020 ◽

Vol 21 (7) ◽

pp. 2313 ◽

Cited By ~ 3

Author(s):

Giuseppina Roscigno ◽

Assunta Cirella ◽

Alessandra Affinito ◽

Cristina Quintavalle ◽

Iolanda Scognamiglio ◽

...

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Tumor Microenvironment ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Negative Regulator ◽

Mammosphere Formation ◽

Incidence And Mortality ◽

Cells Of The Microenvironment

Breast cancer is the most frequent malignancy in females in terms of both incidence and mortality. Underlying the high mortality rate is the presence of cancer stem cells, which divide indefinitely and are resistant to conventional chemotherapies, so causing tumor relapse. In the present study, we identify miR-216a-5p as a downregulated microRNA in breast cancer stem cells vs. the differentiated counterpart. We demonstrate that overexpression of miR-216a-5p impairs stemness markers, mammosphere formation, ALDH activity, and the level of Toll-like receptor 4 (TLR4), which plays a significant role in breast cancer progression and metastasis by leading to the release of pro-inflammatory molecules, such as interleukin 6 (IL-6). Indeed, miR-216a regulates the crosstalk between cancer cells and the cells of the microenvironment, in particular cancer-associated fibroblasts (CAFs), through regulation of the TLR4/IL6 pathway. Thus, miR-216a has an important role in the regulation of stem phenotype, decreasing stem-like properties and affecting the cross-talk between cancer cells and the tumor microenvironment.

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TAB2 Promotes the Stemness and Biological Functions of Cervical Squamous Cell Carcinoma Cells

Stem Cells International ◽

10.1155/2021/6550388 ◽

2021 ◽

Vol 2021 ◽

pp. 1-12

Author(s):

Yijia Zhou ◽

Yuandong Liao ◽

Chunyu Zhang ◽

Junxiu Liu ◽

Wei Wang ◽

...

Keyword(s):

Cervical Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Cancer Progression ◽

Cell Function ◽

Chemotherapy Resistance ◽

Cervical Squamous Cell Carcinoma ◽

Published Data ◽

Cell Functions

Cancer stem cells are a key population participating in the promotion of the cervical cancer progression through interacting with cancer cells. Existing studies have preliminary revealed that cervical cancer stem cells contribute to tumor recurrence and chemotherapy resistance. However, the specific mechanisms involved in regulating cell functions remain largely unknown. Here, we analyzed published data from public databases and our global transcriptome data, thus identifying cancer-related signaling pathways and molecules. According to our findings, upregulated TAB2 was correlated to stem cell-like properties of cervical cancer. Immunohistochemistry staining of TAB2 in normal and cervical cancer tissues was performed. The cell function experiments demonstrated that knockdown of TAB2 reduced the stemness of cervical cancer cells and, importantly, prevented cervical cancer progression. Collectively, the therapeutic scheme targeting TAB2 may provide an option for overcoming tumor relapse and chemoresistance of cervical cancer via obstructing stemness maintenance.

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Matrix Stiffness Modulates Metabolic Interaction Between Human Stromal and Breast Cancer Cells to Stimulate Epithelial Motility

10.21203/rs.3.rs-186889/v1 ◽

2021 ◽

Author(s):

Ivan Ponce ◽

Nelson Garrido ◽

Nicolas Tobar ◽

Patricio C Smith ◽

Francisco Melo ◽

...

Keyword(s):

Breast Cancer ◽

Cancer Cells ◽

Cancer Progression ◽

Stromal Cells ◽

Glucose Transporter ◽

Lactate Production ◽

Normal Breast ◽

Metabolic Reprogramming ◽

Dependent Manner ◽

Functional Link

Abstract Background. Breast tumors belong to the type of desmoplastic lesion in which a stiffer tissue structure is a determinant of breast cancer progression and constitutes a risk factor for breast cancer development. It has been proposed that cancer-associated stromal cells (responsible for this fibrotic phenomenon) are able to metabolize glucose via lactate production, which supports the catabolic metabolism of cancer cells. The aim of this work is to investigate the possible functional link among these two processes.Methods. To measure the effect of matrix rigidity on metabolic determinations, we used compliant elastic polyacrylamide gels as a substrate material to which matrix molecules were covalently-linked. We evaluated metabolite transport in stromal cells using two different FRET nanosensors specific for glucose and lactate. Cell migration/invasion was evaluated using Transwell devices.Results. We show that increased stiffness stimulates lactate production and glucose uptake by mammary fibroblasts. This response correlated with the expression of stromal glucose transporter Glut1 and monocarboxylate transporters MCT4. Moreover, mammary stromal cells cultured on stiff matrices generated soluble factors that stimulated epithelial breast migration in a stiffness-dependent manner.Conclusions. Using a normal breast stromal cell line, we found that a stiffer extracellular matrix favors the acquisition mechanistical properties that promote the metabolic reprograming that also constitute a stimulus for epithelial motility. This new knowledge will help us to better understand the complex relationship between fibrosis, metabolic reprogramming and cancer malignancy.

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Peroxiredoxin II Regulates Cancer Stem Cells and Stemness-Associated Properties of Cancers

Cancers ◽

10.3390/cancers10090305 ◽

2018 ◽

Vol 10 (9) ◽

pp. 305 ◽

Cited By ~ 9

Author(s):

Nisansala Chandimali ◽

Dong Jeong ◽

Taeho Kwon

Keyword(s):

Oxidative Stress ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Redox Status ◽

Cell Phenotype ◽

Therapeutic Effects ◽

Cellular Functions ◽

Unlimited Growth ◽

Current Therapies

Cancer stem cells (CSCs) represent a sub-population of cancer cells with the ability to regulate stemness-associated properties which are specifically responsible for unlimited growth of cancers, generation of diverse cancer cells in differentiated state and resistance to existing chemotherapy and radiotherapy. Even though, current therapies destroy majority of cancer cells, it is believed to leave CSCs without eradicating which may be the conceptualization for chemoresistance and radio-resistance. Reactive oxygen species (ROS) maintain stem cells and regulate the stemness-associated properties of cancers. Beyond the maximum limit, ROS can damage cellular functions of cancers by subjecting them to oxidative stress. Thus, maintenance of ROS level plays an important role in cancers to regulate stemness-associated properties. Peroxiredoxin II (Prx II) is a member of peroxiredoxin antioxidant enzyme family which considers as a regulator of ROS in cellular environments by modulating redox status to maintain CSC phenotype and stemness properties. Prx II has cell type-dependent expression in various types of cancer cells and overexpression or silenced expression of Prx II in cancers is associated with stem cell phenotype and stemness-associated properties via activation or deactivation of various signaling pathways. In this review, we summarized available studies on Prx II expression in cancers and the mechanisms by which Prx II takes parts to regulate CSCs and stemness-associated properties. We further discussed the potential therapeutic effects of altering Prx II expression in cancers for better anticancer strategies by sensitizing cancer cells and stem cells to oxidative stress and inhibiting stemness-associated properties.

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Cross talk between tumor stroma and cancer cells plays a critical role in progressive enrichment of cancer stem cell phenotype in primary breast tumors

10.1101/2020.06.15.152355 ◽

2020 ◽

Author(s):

Ninjit Dhanota ◽

Amanjit Bal ◽

Gurpreet Singh ◽

Sunil K Arora

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Cancer Cells ◽

Stromal Cells ◽

Breast Tumors ◽

Clinicopathological Parameters ◽

Cell Phenotype ◽

Mesenchymal Transition ◽

Tumor Mass

AbstractIn order to delineate the underlying molecular mechanisms responsible for intra tumoral enrichment of BCSCs in aggressive breast tumors, firstly we evaluated the frequency and characteristics of breast cancer stem cells (BCSCs) within the tumor mass as well as in pathologically normal adjacent tissues in primary breast carcinomas of various clinical and histological grades. Then, we evaluated the expression profiles of various genes in non-cancer stem cells from these tumors to delineate the role played by cellular niche in de novo origin and/or expansion of intra-tumoral cancer stem cells.The study included primary tumor and adjacent normal breast tissue specimens from chemotherapy-naïve breast carcinoma patients. The BCSCs, identified as Lin-CD44+CD24- and aldehyde dehydrogenase 1 A1 positive were enumerated. The frequency of intra-tumoral BCSCs was correlated with various clinicopathological parameters of breast cancer. The flow-cytometrically sorted stromal cells and cancer cells from treatment naïve primary breast tumors were processed for gene expression profiling using a custom designed PCR array of genes known to facilitate cancer cell proliferation and disease progression.The frequency of BCSCs within the tumor mass as well as in the adjacent normal tissue correlated significantly with histopathological and molecular grades of tumors indicating a direct relationship of BCSC with aggressive behavior of breast cancer. A significantly higher number of BCSCs was also detected in metastatic LN group as compared to non-metastatic LN. Further, a significantly increased expression of the genes associated with growth factors, cytokines & matricellular proteins in tumors with high BCSCs content (> 5%; Hi-BCSCs tumors) as compared to Lo-BCSC tumors (with <5% intratumoral BCSC content) suggested the possible contribution of stromal cells and cancer cells in intra-tumoral expansion of CSCs. Similarly, a significant up-regulation of genes associated with hypoxia and angiogenesis in Hi-BCSCs tumors further supported the role of hypoxic environment. The expression levels of genes associated with epithelial to mesenchymal transition also followed a similar pattern. On the other hand, downregulated SNAI1 gene (generally upregulated in onset of EMT) in stromal cells of Hi-BCSCs tumors suggests a post EMT environment in Hi-BCSCs tumors.The findings suggest that the molecular crosstalk between the non-BCSC niche cells and the cancer stem cells within the breast cancer microenvironment directly contribute to formation of biologically conducive conditions for expansion of cancer stem cells.

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Role of Aberrant Lipid Metabolism of Cancer Stem Cells in Cancer Progression

Current Cancer Drug Targets ◽

10.2174/1568009619666210316112333 ◽

2021 ◽

Vol 21 ◽

Author(s):

Juan Zhou ◽

Jing Zhao ◽

Chunxia Su

Keyword(s):

Stem Cells ◽

Lipid Metabolism ◽

Cancer Stem Cells ◽

Cancer Progression ◽

Energy Homeostasis ◽

Small Population ◽

Research Field ◽

Metabolic Reprogramming ◽

Cancer Types

: Cancer stem cells (CSCs) represent a small population of cancer cells that are able to self-renew and initiate tumors, which undergo epigenetic, epithelial-mesenchymal, immunological, and metabolic reprogramming to adapt to the tumor microenvironment as well as survive host defense or therapeutic insults. The metabolic reprogramming that accompanies cancer onset is known to be critical for the disease pathogenesis. A coordinated dysregulation of lipid metabolism is observed in nearly all cancer types. In addition to fulfilling basic requirements of structural lipids for membrane synthesis, lipids function importantly as signaling molecules and contribute to energy homeostasis. In this review, we summarize the current progress in the attractive research field of aberrant lipid metabolism regarding CSCs in cancer progression, which provides insights into therapeutic agents targeting CSCs based upon their modulation of lipid metabolism.

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