Cancer Metastasis and Therapeutic Resistance

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cancer Biology and Oncology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 21867

Special Issue Editor

Department of Pharmacology and Toxicology, Indiana University School of Medicine, Simon Comprehensive Cancer Center, Indianapolis, IN, USA
Interests: cancer; metastasis; kinases; cell signaling; therapeutic resistance; autophagy
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Metastasis and resistance to cancer treatments often go hand in hand, relying on overlapping mechanisms that allow cancer to progress from their primary form to more severe disease states. These mechanisms include the activation of signaling pathways, evasion of immune surveillance, and alteration of cell surface receptors. While numerous targets and agents have been uncovered in recent years, cancer cells continue to evade these solutions. In this Special Issue, we aim to present high-quality research in these areas to share within the research community what we have learned, what is new, and what is on the cutting edge of mechanisms that cause metastasis and resistance. We welcome the submission of original research articles and review articles on signaling mechanisms, experimental therapeutics, and clinical observations.

Dr. Elizabeth Yeh
Guest Editor

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Keywords

  • cancer
  • metastasis
  • resistance
  • signaling
  • receptors
  • biomarkers

Published Papers (10 papers)

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Editorial

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3 pages, 190 KiB  
Editorial
Special Issue: Cancer Metastasis and Therapeutic Resistance
by Elizabeth S. Yeh
Biomedicines 2023, 11(5), 1347; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines11051347 - 03 May 2023
Viewed by 981
Abstract
Metastasis and resistance to cancer therapeutics are critical barriers to curing cancer. This special issue entitled “Cancer Metastasis and Therapeutic Resistance” contains nine original contributions. The articles span a variety of human cancers, including breast, lung, brain, prostate, and skin and touch upon [...] Read more.
Metastasis and resistance to cancer therapeutics are critical barriers to curing cancer. This special issue entitled “Cancer Metastasis and Therapeutic Resistance” contains nine original contributions. The articles span a variety of human cancers, including breast, lung, brain, prostate, and skin and touch upon significant areas of interest such as cancer stem cell function, cancer immunology, and glycosylation. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)

Research

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17 pages, 3351 KiB  
Article
Immunotherapy against the Cystine/Glutamate Antiporter xCT Improves the Efficacy of APR-246 in Preclinical Breast Cancer Models
by Giuseppina Barutello, Antonino Di Lorenzo, Alessandro Gasparetto, Chiara Galiazzi, Elisabetta Bolli, Laura Conti and Federica Cavallo
Biomedicines 2022, 10(11), 2843; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112843 - 08 Nov 2022
Cited by 3 | Viewed by 1547
Abstract
Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer [...] Read more.
Breast cancer is the most frequent cancer in women. Despite recent clinical advances, new therapeutic approaches are still required. The cystine-glutamate antiporter xCT, encoded by the SLC7A11 gene, which imports cystine in exchange with glutamate, is a potentially new target for breast cancer therapy, being involved in tumor cell redox balance and resistance to therapies. xCT expression is regulated by the oncosuppressor p53, which is mutated in many breast cancers. Indeed, mutant p53 (mut-p53) can induce xCT post-transcriptional down modulation, rendering mut-p53 tumors susceptible to oxidative damage. Interestingly, the drug APR-246, developed to restore the wild-type function of p53 in tumors harboring its mutation, alters the cell redox balance in a p53-independent way, possibly rendering the cells more sensitive to xCT inhibition. Here, we propose a combinatorial treatment based on xCT immunetargeting and APR-246 treatment as a strategy for tackling breast cancer. We demonstrate that combining the inhibition of xCT with the APR-246 drug significantly decreased breast cancer cell viability in vitro and induced apoptosis and affected cancer stem cells’ self-renewal compared to the single treatments. Moreover, the immunetargeting of xCT through DNA vaccination in combination with APR-246 treatment synergistically hinders tumor progression and prevents lung metastasis formation in vivo. These effects can be mediated by the production of anti-xCT antibodies that are able to induce the antibody dependent cellular cytotoxicity of tumor cells. Overall, we demonstrate that DNA vaccination against xCT can synergize with APR-246 treatment and enhance its therapeutic effect. Thus, APR-246 treatment in combination with xCT immunetargeting may open new perspectives in the management of breast cancer. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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14 pages, 2416 KiB  
Article
Cisplatin Induces Senescent Lung Cancer Cell-Mediated Stemness Induction via GRP78/Akt-Dependent Mechanism
by Nicharat Sriratanasak, Preedakorn Chunhacha, Zin Zin Ei and Pithi Chanvorachote
Biomedicines 2022, 10(11), 2703; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112703 - 26 Oct 2022
Cited by 4 | Viewed by 1558
Abstract
Cellular senescence is linked with chemotherapy resistance. Based on previous studies, GRP78 is a signal transducer in senescent cells. However, the association between GRP78 and stem cell phenotype remains unknown. Cisplatin treatment was clarified to induce cellular senescence leading to stemness induction via [...] Read more.
Cellular senescence is linked with chemotherapy resistance. Based on previous studies, GRP78 is a signal transducer in senescent cells. However, the association between GRP78 and stem cell phenotype remains unknown. Cisplatin treatment was clarified to induce cellular senescence leading to stemness induction via GRP78/Akt signal transduction. H460 cells were treated with 5 μM of cisplatin for 6 days to develop senescence. The colony formation assay and cell cycle analysis were performed. SA-β-galactosidase staining indicated senescence. Western blot analysis and RT-PCR were operated. Immunoprecipitation (IP) and immunocytochemistry assays (ICC) were also performed. Colony-forming activity was completely inhibited, and 87.07% of the cell population was arrested in the G2 phase of the cell cycle. mRNA of p21 and p53 increased approximately by 15.91- and 19.32-fold, respectively. The protein level of p21 and p53 was elevated by 9.57- and 5.9-fold, respectively. In addition, the c-Myc protein level was decreased by 0.2-fold when compared with the non-treatment control. Even though, the total of GRP78 protein was downregulated after cisplatin treatment, but the MTJ1 and downstream regulator, p-Akt/Akt ratio were upregulated by approximately 3.38 and 1.44-fold, respectively. GRP78 and MTJ1 were found at the cell surface membrane. Results showed that the GRP78/MTJ1 complex and stemness markers, including CD44, CD133, Nanog, Oct4, and Sox2, were concomitantly increased in senescent cells. MTJ1 anchored GRP78, facilitating the signal transduction of stem-like phenotypes. The strategy that could interrupt the binding between these crucial proteins or inhibit the translocation of GRP78 might beuseful for cancer therapy. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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16 pages, 2672 KiB  
Article
Anti-Tumor Functions of Prelatent Antithrombin on Glioblastoma Multiforme Cells
by Julia Peñas-Martínez, Ginés Luengo-Gil, Salvador Espín, Nataliya Bohdan, Carmen Ortega-Sabater, Maria Carmen Ródenas, David Zaragoza-Huesca, María José López-Andreo, Carme Plasencia, Vicente Vicente, Alberto Carmona-Bayonas and Irene Martínez-Martínez
Biomedicines 2021, 9(5), 523; https://doi.org/10.3390/biomedicines9050523 - 07 May 2021
Cited by 5 | Viewed by 2329
Abstract
Antithrombin, the main physiological inhibitor of the coagulation cascade, exerts anti-tumor effects on glioblastoma multiforme cells. Antithrombin has different conformations: native, heparin-activated, prelatent, latent, and cleaved. The prelatent form has an intermediate affinity between latent and native antithrombin, although it is the most [...] Read more.
Antithrombin, the main physiological inhibitor of the coagulation cascade, exerts anti-tumor effects on glioblastoma multiforme cells. Antithrombin has different conformations: native, heparin-activated, prelatent, latent, and cleaved. The prelatent form has an intermediate affinity between latent and native antithrombin, although it is the most antiangiogenic form. Herein, we investigate the effect of this conformation on the tumorigenic processes of glioblastoma multiforme cells. Antithrombin forms were purified by chromatography. Chromogenic/fluorogenic assays were carried out to evaluate enteropeptidase and hepsin inhibition, two serine proteases involved in these processes. Wound healing, Matrigel invasion and BrdU incorporation assays were performed to study migration, invasion and proliferation. E-cadherin, Vimentin, VEGFA, pAKT, STAT3, pSTAT3, and pERK1/2 expression was assessed by Western blot and/or qRT-PCR. Prelatent antithrombin inhibited both enteropeptidase and hepsin, although it was less efficient than the native conformation. Exposure to prelatent antithrombin significantly reduced migration and invasion but not proliferation of U-87 MG, being the conformation most efficient on migration. Prelatent antithrombin down-regulated VEGFA, pSTAT3, and pERK1/2 expression in U-87 MG cells. Our work elucidates that prelatent antithrombin has surprisingly versatile anti-tumor properties in U-87 MG glioblastoma multiforme cells. This associates with resistance pathway activation, the decreased expression of tumorigenic proteins, and increased angiogenesis, postulating the existence of a new, formerly unknown receptor with potential therapeutic implications. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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14 pages, 3510 KiB  
Article
GBP5 Repression Suppresses the Metastatic Potential and PD-L1 Expression in Triple-Negative Breast Cancer
by Shun-Wen Cheng, Po-Chih Chen, Min-Hsuan Lin, Tzong-Rong Ger, Hui-Wen Chiu and Yuan-Feng Lin
Biomedicines 2021, 9(4), 371; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9040371 - 01 Apr 2021
Cited by 13 | Viewed by 2854
Abstract
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic [...] Read more.
Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype because of its high metastatic potential. Immune evasion due to aberrant expression of programmed cell death ligand 1 (PD-L1) has also been reported recently in metastatic TNBC. However, the mechanism underlying metastatic progression and PD-L1 upregulation in TNBC is still largely unknown. Here, we found that guanylate binding protein 5 (GBP5) is expressed in higher levels in TNBC tissues than in non-TNBC and normal mammary tissues and serves as a poorer prognostic marker in breast cancer patients. Transwell cultivation indicated that GBP5 expression is causally related to cellular migration ability in the detected TNBC cell lines. Moreover, the computational simulation of the gene set enrichment analysis (GSEA) program against the GBP5 signature generated from its coexpression with other somatic genes in TNBC revealed that GBP5 upregulation may be associated with the activation of interferon gamma (IFN-γ)-responsive and NF-κB-related signaling cascades. In addition, we found that the coexpression of GBP5 with PD-L1 was significantly positive correlation in TNBC tissues. Robustly, our data showed that GBP5 knockdown in TNBC cells harboring a higher GBP5 level dramatically suppresses the number of migrated cells, the activity of IFN-γ/STAT1 and TNF-α/NF-κB signaling axes, and the expression of PD-L1. Importantly, the signature combining a higher GBP5 and PD-L1 level predicted the shortest time interval of brain metastasis in breast cancer patients. These findings not only uncover the oncogenic function of GBP5 but also provide a new strategy to combat metastatic/immunosuppressive TNBC by targeting GBP5 activity. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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17 pages, 22126 KiB  
Article
Rhosin Suppressed Tumor Cell Metastasis through Inhibition of Rho/YAP Pathway and Expression of RHAMM and CXCR4 in Melanoma and Breast Cancer Cells
by Masanobu Tsubaki, Shuuji Genno, Tomoya Takeda, Takuya Matsuda, Naoto Kimura, Yuuma Yamashita, Yuusuke Morii, Kazunori Shimomura and Shozo Nishida
Biomedicines 2021, 9(1), 35; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines9010035 - 04 Jan 2021
Cited by 13 | Viewed by 3526
Abstract
The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear [...] Read more.
The high mortality rate of cancer is strongly correlated with the development of distant metastases at secondary sites. Although Rho GTPases, such as RhoA, RhoB, RhoC, and RhoE, promote tumor metastasis, the main roles of Rho GTPases remain unidentified. It is also unclear whether rhosin, a Rho inhibitor, acts by suppressing metastasis by a downstream inhibition of Rho. In this study, we investigated this mechanism of metastasis in highly metastatic melanoma and breast cancer cells, and the mechanism of inhibition of metastasis by rhosin. We found that rhosin suppressed the RhoA and RhoC activation, the nuclear localization of YAP, but did not affect ERK1/2, Akt, or NF-κB activation in the highly metastatic cell lines B16BL6 and 4T1. High expression of YAP was associated with poor overall and recurrence-free survival in patients with breast cancer or melanoma. Treatment with rhosin inhibited lung metastasis in vivo. Moreover, rhosin inhibited tumor cell adhesion to the extracellular matrix via suppression of RHAMM expression, and inhibited SDF-1-induced cell migration and invasion by decreasing CXCR4 expression in B16BL6 and 4T1 cells. These results suggest that the inhibition of RhoA/C-YAP pathway by rhosin could be an extremely useful therapeutic approach in patients with melanoma and breast cancer. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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10 pages, 1075 KiB  
Communication
NF-κB Signaling Is Regulated by Fucosylation in Metastatic Breast Cancer Cells
by Emma H. Doud, Trupti Shetty, Melissa Abt, Amber L. Mosley, Timothy W. Corson, Anand Mehta and Elizabeth S. Yeh
Biomedicines 2020, 8(12), 600; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8120600 - 12 Dec 2020
Cited by 4 | Viewed by 2046
Abstract
A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis [...] Read more.
A growing body of evidence indicates that the levels of fucosylation correlate with breast cancer progression and contribute to metastatic disease. However, very little is known about the signaling and functional outcomes that are driven by fucosylation. We performed a global proteomic analysis of 4T1 metastatic mammary tumor cells in the presence and absence of a fucosylation inhibitor, 2-fluorofucose (2FF). Of significant interest, pathway analysis based on our results revealed a reduction in the NF-κB and TNF signaling pathways, which regulate the inflammatory response. NF-κB is a transcription factor that is pro-tumorigenic and a prime target in human cancer. We validated our results, confirming that treatment of 4T1 cells with 2FF led to a decrease in NF-κB activity through increased IκBα. Based on these observations, we conclude that fucosylation is an important post-translational modification that governs breast cancer cell signaling. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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11 pages, 1748 KiB  
Communication
Targeting Stereotactic Body Radiotherapy on Metabolic PET- and Immuno-PET-Positive Vertebral Metastases
by Baptiste Pichon, Caroline Rousseau, Audrey Blanc-Lapierre, Gregory Delpon, Ludovic Ferrer, Vincent Libois, Matthieu Le Turnier, Cédric Lenoble, Caroline Bodet-Milin, David M. Goldenberg, Françoise Kraeber-Bodere and Stéphane Supiot
Biomedicines 2020, 8(12), 548; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines8120548 - 28 Nov 2020
Cited by 8 | Viewed by 1977
Abstract
(1) Background: Stereotactic body radiotherapy (SBRT) for vertebral metastases (VM) allows the delivery of high radiation doses to tumors while sparing the spinal cord. We report a new approach to clinical target volume (CTV) delineation based on anti-carcinoembryonic antigen (CEA) positron emission tomography [...] Read more.
(1) Background: Stereotactic body radiotherapy (SBRT) for vertebral metastases (VM) allows the delivery of high radiation doses to tumors while sparing the spinal cord. We report a new approach to clinical target volume (CTV) delineation based on anti-carcinoembryonic antigen (CEA) positron emission tomography (pretargeted immuno-PET; “iPET”) in patients with metastatic breast cancer (BC) or medullary thyroid cancer (MTC). (2) Methods: All patients underwent iPET, spine magnetic resonance imaging (MRI), and positron emission tomography-computed tomography (PET-CT) using 18F-deoxyglucose (FDG) for BC or 18F-dihydroxy-phenylalanine (F-DOPA) for MTC. Vertebrae locations and vertebral segments of lesions were recorded and the impact on CTV delineation was evaluated. (3) Results: Forty-six VM eligible for SBRT following iPET were evaluated in eight patients (five BC, three MTC). Eighty-one vertebral segments were detected using MRI, 26 with FDG or F-DOPA PET/CT, and 70 using iPET. iPET was able to detect more lesions than MRI for vertebral bodies (44 vs. 34). iPET-based delineation modified MRI-based CTV in 70% (32/46) of cases. (4) Conclusion: iPET allows a precise mapping of affected VM segments, and adds complementary information to MRI in the definition of candidate volumes for VM SBRT. iPET may facilitate determining target volumes for treatment with stereotactic body radiotherapy in metastatic vertebral disease. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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Review

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30 pages, 2420 KiB  
Review
Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment
by Ethan J. Kilmister, Sabrina P. Koh, Freya R. Weth, Clint Gray and Swee T. Tan
Biomedicines 2022, 10(11), 2988; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10112988 - 21 Nov 2022
Cited by 6 | Viewed by 2553
Abstract
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)—a small population of highly tumorigenic cancer cells with [...] Read more.
Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)—a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/β-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a ‘silver-bullet’ single-target approach. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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Other

8 pages, 1380 KiB  
Brief Report
Osteoblast Secretome Modulated by Abiraterone Treatment Affects Castration Resistant Prostate Cancer Cell Proliferation
by Michele Iuliani, Sonia Simonetti, Giulia Ribelli, Silvia Cavaliere, Bruno Vincenzi, Giuseppe Tonini, Francesco Pantano and Daniele Santini
Biomedicines 2022, 10(9), 2154; https://0-doi-org.brum.beds.ac.uk/10.3390/biomedicines10092154 - 01 Sep 2022
Cited by 1 | Viewed by 1299
Abstract
Abiraterone is a selective inhibitor of androgen biosynthesis approved for the treatment of metastatic patients affected by castration-resistant or castration-sensitive prostate cancer. Intriguingly, clinical data revealed that abiraterone also delayed disease progression in bone improving bone-related endpoints. Our group has previously demonstrated in [...] Read more.
Abiraterone is a selective inhibitor of androgen biosynthesis approved for the treatment of metastatic patients affected by castration-resistant or castration-sensitive prostate cancer. Intriguingly, clinical data revealed that abiraterone also delayed disease progression in bone improving bone-related endpoints. Our group has previously demonstrated in vitro a direct effect of abiraterone on osteoclast and osteoblast function suggesting its ability to modulate bone microenvironment. Here, we performed an extensive proteomic analysis to investigate how abiraterone influences osteoblast cell secretome and, consequently, osteoblast/prostate cancer cells interaction. A panel of 507 soluble molecules were analyzed in osteoblast conditioned media (OCM) obtained from osteoblast treated or not with abiraterone. Subsequently, OCM was added to prostate cancer cells to investigate its potential effect on prostate cancer cell proliferation and androgen receptor (AR) activation status. Out of 507 screened molecules, 39 of them were differentially expressed in OCM from osteoblasts treated with abiraterone (OCM ABI) compared to OCM obtained from untreated OBs (OCM CTRL). Pathway enrichment analysis revealed that abiraterone down-modulated the release of specific osteoblast soluble factors, positively associated with cell proliferation pathways (false discovery rate adjusted p-value = 0.0019). In vitro validation data showed that OCM ABI treatment significantly reduced cancer proliferation in C4-2B cells (p = 0.022), but not in AR- negative PC-3 cells. Moreover, we also found a reduction in AR activation in C4-2B cells (p = 0.017) confirming the “indirect” anti-tumor AR-dependent effect of abiraterone mediated by osteoblasts. This study provides the first evidence of an additional antitumor effect of abiraterone through the modulation of multiple osteoblast proliferative signals. Full article
(This article belongs to the Special Issue Cancer Metastasis and Therapeutic Resistance)
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