Towards targeting of shared mechanisms of cancer metastasis and therapy resistance

Cancer metastasis and therapy resistance are the foremost hurdles in oncology at the moment. This review aims to pinpoint the functional aspects of a unique multifaceted glycosylated molecule in both intracellular and extracellular compartments of a cell namely galectin-3 along with its metastatic potential in different types of cancer. All materials reviewed here were collected through the search engines PubMed, Scopus, and Google scholar. Among the 15 galectins identified, the chimeric gal-3 plays an indispensable role in the differentiation, transformation, and multi-step process of tumor metastasis. It has been implicated in the molecular mechanisms that allow the cancer cells to survive in the intravascular milieu and promote tumor cell extravasation, ultimately leading to metastasis. Gal-3 has also been found to have a pivotal role in immune surveillance and pro-angiogenesis and several studies have pointed out the importance of gal-3 in establishing a resistant phenotype, particularly through the epithelial-mesenchymal transition process. Additionally, some recent findings suggest the use of gal-3 inhibitors in overcoming therapeutic resistance. All these reports suggest that the deregulation of these specific lectins at the cellular level could inhibit cancer progression and metastasis. A more systematic study of glycosylation in clinical samples along with the development of selective gal-3 antagonists inhibiting the activity of these molecules at the cellular level offers an innovative strategy for primary cancer prevention.

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Tissue-specific tregs in cancer metastasis: opportunities for precision immunotherapy

Cellular and Molecular Immunology ◽

10.1038/s41423-021-00742-4 ◽

2021 ◽

Author(s):

Laura A. Huppert ◽

Michael D. Green ◽

Luke Kim ◽

Christine Chow ◽

Yan Leyfman ◽

...

Keyword(s):

Cancer Immunotherapy ◽

Cancer Metastasis ◽

Metastatic Cancer ◽

High Volume ◽

Therapy Resistance ◽

Term Treatment ◽

The Body ◽

Tissue Specific ◽

Tissue Repair And Regeneration ◽

Long Term Treatment

AbstractDecades of advancements in immuno-oncology have enabled the development of current immunotherapies, which provide long-term treatment responses in certain metastatic cancer patients. However, cures remain infrequent, and most patients ultimately succumb to treatment-refractory metastatic disease. Recent insights suggest that tumors at certain organ sites exhibit distinctive response patterns to immunotherapy and can even reduce antitumor immunity within anatomically distant tumors, suggesting the activation of tissue-specific immune tolerogenic mechanisms in some cases of therapy resistance. Specialized immune cells known as regulatory T cells (Tregs) are present within all tissues in the body and coordinate the suppression of excessive immune activation to curb autoimmunity and maintain immune homeostasis. Despite the high volume of research on Tregs, the findings have failed to reconcile tissue-specific Treg functions in organs, such as tolerance, tissue repair, and regeneration, with their suppression of local and systemic tumor immunity in the context of immunotherapy resistance. To improve the understanding of how the tissue-specific functions of Tregs impact cancer immunotherapy, we review the specialized role of Tregs in clinically common and challenging organ sites of cancer metastasis, highlight research that describes Treg impacts on tissue-specific and systemic immune regulation in the context of immunotherapy, and summarize ongoing work reporting clinically feasible strategies that combine the specific targeting of Tregs with systemic cancer immunotherapy. Improved knowledge of Tregs in the framework of their tissue-specific biology and clinical sites of organ metastasis will enable more precise targeting of immunotherapy and have profound implications for treating patients with metastatic cancer.

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MiR-205 Dysregulations in Breast Cancer: The Complexity and Opportunities

Non-Coding RNA ◽

10.3390/ncrna5040053 ◽

2019 ◽

Vol 5 (4) ◽

pp. 53 ◽

Cited By ~ 9

Author(s):

Xiao ◽

Humphries ◽

Yang ◽

Wang

Keyword(s):

Breast Cancer ◽

Cell Proliferation ◽

Cancer Cell ◽

Target Gene ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Metastatic Breast ◽

Therapy Resistance ◽

Cancer Cell Proliferation ◽

Mesenchymal Transition

MicroRNAs (miRNAs) are endogenous non-coding small RNAs that downregulate target gene expression by imperfect base-pairing with the 3′ untranslated regions (3′UTRs) of target gene mRNAs. MiRNAs play important roles in regulating cancer cell proliferation, stemness maintenance, tumorigenesis, cancer metastasis, and cancer therapeutic resistance. While studies have shown that dysregulation of miRNA-205-5p (miR-205) expression is controversial in different types of human cancers, it is generally observed that miR-205-5p expression level is downregulated in breast cancer and that miR-205-5p exhibits a tumor suppressive function in breast cancer. This review focuses on the role of miR-205-5p dysregulation in different subtypes of breast cancer, with discussions on the effects of miR-205-5p on breast cancer cell proliferation, epithelial–mesenchymal transition (EMT), metastasis, stemness and therapy-resistance, as well as genetic and epigenetic mechanisms that regulate miR-205-5p expression in breast cancer. In addition, the potential diagnostic and therapeutic value of miR-205-5p in breast cancer is also discussed. A comprehensive list of validated miR-205-5p direct targets is presented. It is concluded that miR-205-5p is an important tumor suppressive miRNA capable of inhibiting the growth and metastasis of human breast cancer, especially triple negative breast cancer. MiR-205-5p might be both a potential diagnostic biomarker and a therapeutic target for metastatic breast cancer.

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NRF2 activates a partial epithelial-mesenchymal transition and is maximally present in a hybrid epithelial/mesenchymal phenotype

Integrative Biology ◽

10.1093/intbio/zyz021 ◽

2019 ◽

Vol 11 (6) ◽

pp. 251-263 ◽

Cited By ~ 28

Author(s):

Federico Bocci ◽

Satyendra C Tripathi ◽

Samuel A Vilchez Mercedes ◽

Jason T George ◽

Julian P Casabar ◽

...

Keyword(s):

Cancer Cells ◽

Cancer Metastasis ◽

Epithelial Mesenchymal Transition ◽

Therapy Resistance ◽

Collective Cell Migration ◽

Mesenchymal Transition ◽

Regulatory Circuit ◽

Clinical Records ◽

E Cadherin

Abstract The epithelial-mesenchymal transition (EMT) is a key process implicated in cancer metastasis and therapy resistance. Recent studies have emphasized that cells can undergo partial EMT to attain a hybrid epithelial/mesenchymal (E/M) phenotype – a cornerstone of tumour aggressiveness and poor prognosis. These cells can have enhanced tumour-initiation potential as compared to purely epithelial or mesenchymal ones and can integrate the properties of cell-cell adhesion and motility that facilitates collective cell migration leading to clusters of circulating tumour cells (CTCs) – the prevalent mode of metastasis. Thus, identifying the molecular players that can enable cells to maintain a hybrid E/M phenotype is crucial to curb the metastatic load. Using an integrated computational-experimental approach, we show that the transcription factor NRF2 can prevent a complete EMT and instead stabilize a hybrid E/M phenotype. Knockdown of NRF2 in hybrid E/M non-small cell lung cancer cells H1975 and bladder cancer cells RT4 destabilized a hybrid E/M phenotype and compromised the ability to collectively migrate to close a wound in vitro. Notably, while NRF2 knockout simultaneously downregulated E-cadherin and ZEB-1, overexpression of NRF2 enriched for a hybrid E/M phenotype by simultaneously upregulating both E-cadherin and ZEB-1 in individual RT4 cells. Further, we predict that NRF2 is maximally expressed in hybrid E/M phenotype(s) and demonstrate that this biphasic dynamic arises from the interconnections among NRF2 and the EMT regulatory circuit. Finally, clinical records from multiple datasets suggest a correlation between a hybrid E/M phenotype, high levels of NRF2 and its targets and poor survival, further strengthening the emerging notion that hybrid E/M phenotype(s) may occupy the ‘metastatic sweet spot’.

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The Role of Cancer Stem Cells in the Organ Tropism of Breast Cancer Metastasis: A Mechanistic Balance between the “Seed” and the “Soil”?

International Journal of Breast Cancer ◽

10.1155/2012/209748 ◽

2012 ◽

Vol 2012 ◽

pp. 1-12 ◽

Cited By ~ 11

Author(s):

Jenny E. Chu ◽

Alison L. Allan

Keyword(s):

Breast Cancer ◽

Stem Cells ◽

Cancer Stem Cells ◽

Metastatic Disease ◽

Cancer Metastasis ◽

Metastatic Breast ◽

Therapy Resistance ◽

Breast Cancer Metastasis ◽

Specific Pattern ◽

Organ Tropism

Breast cancer is a prevalent disease worldwide, and the majority of deaths occur due to metastatic disease. Clinical studies have identified a specific pattern for the metastatic spread of breast cancer, termed organ tropism; where preferential secondary sites include lymph node, bone, brain, lung, and liver. A rare subpopulation of tumor cells, the cancer stem cells (CSCs), has been hypothesized to be responsible for metastatic disease and therapy resistance. Current treatments are highly ineffective against metastatic breast cancer, likely due to the innate therapy resistance of CSCs and the complex interactions that occur between cancer cells and their metastatic microenvironments. A better understanding of these interactions is essential for the development of novel therapeutic targets for metastatic disease. This paper summarizes the characteristics of breast CSCs and their potential metastatic microenvironments. Furthermore, it raises the question of the existence of a CSC niche and highlights areas for future investigation.

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Deficiency of Ku Induces Host Cell Exploitation in Human Cancer Cells

Frontiers in Cell and Developmental Biology ◽

10.3389/fcell.2021.651818 ◽

2021 ◽

Vol 9 ◽

Author(s):

Okay Saydam ◽

Nurten Saydam

Keyword(s):

Host Cell ◽

Cancer Cells ◽

Cell Line ◽

Cancer Cell ◽

Cancer Metastasis ◽

Human Cancer ◽

Therapy Resistance ◽

Host Cells ◽

Human Cancer Cells ◽

Parasitic Lifestyle

Cancer metastasis is the major cause of death from cancer (Massague and Obenauf, 2016; Steeg, 2016). The extensive genetic heterogeneity and cellular plasticity of metastatic tumors set a prime barrier for the current cancer treatment protocols (Boumahdi and de Sauvage, 2020). In addition, acquired therapy resistance has become an insurmountable obstacle that abolishes the beneficial effects of numerous anti-cancer regimens (De Angelis et al., 2019; Boumahdi and de Sauvage, 2020). Here we report that deficiency of Ku leads to the exploitation of host cells in human cancer cell line models. We found that, upon conditional deletion of XRCC6 that codes for Ku70, HCT116 human colorectal cancer cells gain a parasitic lifestyle that is characterized by the continuous cycle of host cell exploitation. We also found that DAOY cells, a human medulloblastoma cell line, innately lack nuclear Ku70/Ku86 proteins and utilize the host-cell invasion/exit mechanism for maintenance of their survival, similarly to the Ku70 conditionally-null HCT116 cells. Our study demonstrates that a functional loss of Ku protein promotes an adaptive, opportunistic switch to a parasitic lifestyle in human cancer cells, providing evidence for a previously unknown mechanism of cell survival in response to severe genomic stress. We anticipate that our study will bring a new perspective for understanding the mechanisms of cancer cell evolution, leading to a shift in the current concepts of cancer therapy protocols directed to the prevention of cancer metastasis and therapy resistance.

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Long Non-Coding RNA: Dual Effects on Breast Cancer Metastasis and Clinical Applications

Cancers ◽

10.3390/cancers11111802 ◽

2019 ◽

Vol 11 (11) ◽

pp. 1802 ◽

Cited By ~ 8

Author(s):

Qi-Yuan Huang ◽

Guo-Feng Liu ◽

Xian-Ling Qian ◽

Li-Bo Tang ◽

Qing-Yun Huang ◽

...

Keyword(s):

Breast Cancer ◽

Distant Metastasis ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Therapy Resistance ◽

Breast Cancer Metastasis ◽

Mesenchymal Transition ◽

Non Coding Rna ◽

Regulatory Effects ◽

Long Non Coding Rna

As a highly heterogeneous malignancy, breast cancer (BC) has become the most significant threat to female health. Distant metastasis and therapy resistance of BC are responsible for most of the cases of mortality and recurrence. Distant metastasis relies on an array of processes, such as cell proliferation, epithelial-to-mesenchymal transition (EMT), mesenchymal-to-epithelial transition (MET), and angiogenesis. Long non-coding RNA (lncRNA) refers to a class of non-coding RNA with a length of over 200 nucleotides. Currently, a rising number of studies have managed to investigate the association between BC and lncRNA. In this study, we summarized how lncRNA has dual effects in BC metastasis by regulating invasion, migration, and distant metastasis of BC cells. We also emphasize that lncRNA has crucial regulatory effects in the stemness and angiogenesis of BC. Clinically, some lncRNAs can regulate chemotherapy sensitivity in BC patients and may function as novel biomarkers to diagnose or predict prognosis for BC patients. The exact impact on clinical relevance deserves further study. This review can be an approach to understanding the dual effects of lncRNAs in BC, thereby linking lncRNAs to quasi-personalized treatment in the future.

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Editorial: LncRNAs in Cancer Metastasis and Therapy Resistance

Frontiers in Oncology ◽

10.3389/fonc.2021.813274 ◽

2021 ◽

Vol 11 ◽

Author(s):

Aamir Ahmad ◽

Palmiro Poltronieri ◽

Shahab Uddin

Keyword(s):

Cancer Metastasis ◽

Therapy Resistance

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Stroma transcriptomic and proteomic profile of prostate cancer metastasis xenograft models reveals conservation of bone microenvironment signatures

10.1101/2020.04.03.018143 ◽

2020 ◽

Author(s):

S. Karkampouna ◽

M.R. De Filippo ◽

C.Y. Ng ◽

I. Klima ◽

E. Zoni ◽

...

Keyword(s):

Prostate Cancer ◽

Bone Metastasis ◽

Cancer Metastasis ◽

Gene Expression Pattern ◽

Therapy Resistance ◽

Mouse Cell ◽

Diagnostic Value ◽

Specific Reference ◽

Xenograft Models

ABSTRACTProstate cancer (PCa) is the second leading cause of cancer-associated death in men with therapy resistance acquisition to androgen deprivation treatment and metastasis progression. Understanding the mechanisms of tumor progression to metastatic stage is necessary for the design of therapeutic and prognostic schemes. The main objective of the current study is to determine, using transcriptomic and proteomic analyses on patient derived-xenograft models, whether differentially aggressive PCa tumors predispose their microenvironment (stroma) to a metastatic gene expression pattern, and how this information could be applied in prognostics. Transcriptomic profiling (RNA Sequencing) was performed on PCa PDX models representing different disease stages; BM18 (androgen dependent bone metastasis) and LAPC9 (androgen independent bone metastasis). Using organism-specific reference databases, the human-specific transcriptome, representing the tumor, was identified and separated from the mouse-specific transcriptome (representing the contributing stroma counterpart) from the same PDX tumor samples. To identify proteome changes in the tumor (human) versus the stroma (mouse), we performed human and mouse cell separation using the MACS mouse depletion sorting kit, and subjected protein lysates to quantitative TMT labeling and mass spectrometry. We show that tenascin C is one of the most abundant stromal genes in bone metastasis PCa PDXs, is modulated by androgen levels in vivo and is highly expressed in castration resistant LAPC9 PDX compared to castration sensitive BM18 PDX. Tissue microarray of primary PCa samples (N=210) was used to evaluate the potential of TNC to act as a metastasis prognosis marker. Low number of TNC-positive cells were associated with statistically significant clinical progression to local recurrence or metastasis, compared to high TNC-positive group. Our data showed that metastatic PCa PDXs that differ in androgen sensitivity trigger a differential stroma response suggesting that stroma was influenced by tumor cues. Selected stromal markers of osteoblastic PCa induced bone metastases, were induced in the microenvironment of the host organism in metastatic xenografts, although implanted in a non-bone site, indicating a conserved mechanism of tumor cells to induce a stromal pre-metastatic signature with high potential prognostic or diagnostic value.

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The Depletion of the “Don’t-Eat-Me” Signal CD47 Increases Radiosensitivity through Phenotypical Attenuation of Cancer Stem Cell and EMT Properties in Oral Squamous Cell Carcinoma Cells

10.20944/preprints201907.0079.v1 ◽

2019 ◽

Author(s):

Shin Pai ◽

Oluwaseun Adebayo Bamodu ◽

Yen-Kuang Lin ◽

Chun-Shu Lin ◽

Pei-Yi Chu ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Oral Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Cancer Metastasis ◽

Epithelial To Mesenchymal Transition ◽

Ectopic Expression ◽

Underlying Mechanism ◽

Therapy Resistance ◽

Mesenchymal Transition

Background: Oral squamous cell carcinoma (OSCC), with poor prognosis and high mortality rates, is one of the most diagnosed head and neck cancers. Cancer stem cells (CSCs) - epithelial-to-mesenchymal transition (EMT) loop is increasingly implicated in the therapy-resistance, relapse, and metastasis of OSCC patients. Accumulating evidence indicate that aberrantly expressed CD47 is associated with cell-death evasion, invasion and cancer metastasis; however, the role of CD47 in the modulation of CSCs-like phenotypes, including therapy-resistance and metastasis, with its underlying mechanism in OSCC remains largely underexplored. Methods: This study investigated the CSCs- modulating potential of CD47 in OSCC cell lines SAS, TW2.6, HSC-3 and FaDu using bioinformatics approach, immunoblotting, immunofluorescence staining, migration, invasion, colony and orosphere formation, as well as radiosensitivity assays. Results: We demonstrated that the characteristic ectopic expression of CD47 in OSCC patients was associated with ~ 20% 2-year survival disadvantage (p = 0.01) and positively correlated with the expression of pluripotency factors; while shRNA silencing of CD47 significantly suppressed cell viability and markedly inhibited orosphere formation, resulting in smaller and fewer orospheres, and downregulated CD133, SOX2, OCT4 and c-Myc mRNA and protein expression levels. We also showed that CD47 downregulation attenuates EMT, migration and clonogenicity of OSCC cells, with associated E-cadherin upregulation and suppression of Vimentin, Slug, Snail, and N-cadherin expression. Conclusion: Of therapeutic relevance, combined with radiotherapy, CD47 knockdown enhanced the anti-OSCC effect of radiotherapy. Thus, we demonstrate the therapeutic feasibility of a CD47-mediated anti-CSCs strategy, and suggest a role for CD47 suppression in potentiating the therapeutic efficacy of radiation therapy in OSCC patients.

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