Advances in biological treatment of melanoma

Biological therapy involves the use of living organisms, substances derived from living organisms, or laboratory-produced versions of such substances to treat disease. Metastatic disease have a grave prognosis in comparison to early stage metastatic cancer where surgical treatment can benefit the patients thus traditional chemotherapy regimens have been found to offer relatively little survival benefit. Treatment of advanced or metastatic melanoma includes involvement of biological modalities such as immunotherapeutic approaches, targeted therapies and epigenetic modification therapies. The goal of immunotherapy for cancer is to provide an effective anticancer immune response. These biological therapies restore or increase the activities of specific immune-system components and counteract immunosuppressive signals produced by cancer cells. Monoclonal antibodies, are laboratory-produced antibodies that bind to specific antigens expressed by cells, such as a protein that is present on the surface of cancer cells but is absent from normal cells. They interfere with the action of proteins that are necessary for tumor growth. When bound to bevacizumab, VEGF cannot interact with its cellular receptor, preventing the signaling that leads to the growth of new blood vessels. MAb’s that bind to cell surface growth factor receptors prevent the targeted receptors from sending their normal growth-promoting signals. The targeted therapeutic agents modulate specific pro-oncogenic mutations such as v-Raf murine sarcoma viral oncogene homolog B (BRAF), MEK inhibitors and CDK4/CDK6, PTEN and GNAQ/GNA11 genes. This review summarizes the biological agents and newer modalities of treatments, and their recent advancements and contributions in the treatment of patients with metastatic melanoma.

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Amoebic Foraging Model of Metastatic Cancer Cells

Symmetry ◽

10.3390/sym13071140 ◽

2021 ◽

Vol 13 (7) ◽

pp. 1140

Author(s):

Daiki Andoh ◽

Yukio-Pegio Gunji

Keyword(s):

Bayesian Inference ◽

Cancer Cells ◽

Metastatic Cancer ◽

Gait Patterns ◽

Lévy Walk ◽

Levy Walk ◽

Unicellular Organisms ◽

Living Organisms ◽

Walk Algorithm ◽

Metastatic Cancer Cells

The Lévy walk is a pattern that is often seen in the movement of living organisms; it has both ballistic and random features and is a behavior that has been recognized in various animals and unicellular organisms, such as amoebae, in recent years. We proposed an amoeba locomotion model that implements Bayesian and inverse Bayesian inference as a Lévy walk algorithm that balances exploration and exploitation, and through a comparison with general random walks, we confirmed its effectiveness. While Bayesian inference is expressed only by P(h) = P(h|d), we introduce inverse Bayesian inference expressed as P(d|h) = P(d) in a symmetry fashion. That symmetry contributes to balancing contracting and expanding the probability space. Additionally, the conditions of various environments were set, and experimental results were obtained that corresponded to changes in gait patterns with respect to changes in the conditions of actual metastatic cancer cells.

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Unique cellular protrusions mediate breast cancer cell migration by tethering to osteogenic cells

npj Breast Cancer ◽

10.1038/s41523-020-00183-8 ◽

2020 ◽

Vol 6 (1) ◽

Author(s):

Aaron M. Muscarella ◽

Wei Dai ◽

Patrick G. Mitchell ◽

Weijie Zhang ◽

Hai Wang ◽

...

Keyword(s):

Gap Junctions ◽

Cancer Cells ◽

Epithelial Mesenchymal Transition ◽

Early Stage ◽

Metastatic Cancer ◽

Disseminated Tumor Cells ◽

Migration And Invasion ◽

Mesenchymal Transition ◽

Osteogenic Cells ◽

Cellular Protrusion

Abstract Migration and invasion are key properties of metastatic cancer cells. These properties can be acquired through intrinsic reprogramming processes such as epithelial-mesenchymal transition. In this study, we discovered an alternative “migration-by-tethering” mechanism through which cancer cells gain the momentum to migrate by adhering to mesenchymal stem cells or osteoblasts. This tethering is mediated by both heterotypic adherens junctions and gap junctions, and leads to a unique cellular protrusion supported by cofilin-coated actin filaments. Inhibition of gap junctions or depletion of cofilin reduces migration-by-tethering. We observed evidence of these protrusions in bone segments harboring experimental and spontaneous bone metastasis in animal models. These data exemplify how cancer cells may acquire migratory ability without intrinsic reprogramming. Furthermore, given the important roles of osteogenic cells in early-stage bone colonization, our observations raise the possibility that migration-by-tethering may drive the relocation of disseminated tumor cells between different niches in the bone microenvironment.

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Normal cells repel WWOX-negative or -dysfunctional cancer cells via WWOX cell surface epitope 286-299

Communications Biology ◽

10.1038/s42003-021-02271-2 ◽

2021 ◽

Vol 4 (1) ◽

Author(s):

Yu-An Chen ◽

Yong-Da Sie ◽

Tsung-Yun Liu ◽

Hsiang-Ling Kuo ◽

Pei-Yi Chou ◽

...

Keyword(s):

Cell Surface ◽

Cancer Cells ◽

Room Temperature ◽

Metastatic Cancer ◽

Normal Cells ◽

Tgfβ Receptor ◽

Membrane Type ◽

Cell Invasiveness ◽

And Control ◽

Metastatic Cancer Cells

AbstractMetastatic cancer cells are frequently deficient in WWOX protein or express dysfunctional WWOX (designated WWOXd). Here, we determined that functional WWOX-expressing (WWOXf) cells migrate collectively and expel the individually migrating WWOXd cells. For return, WWOXd cells induces apoptosis of WWOXf cells from a remote distance. Survival of WWOXd from the cell-to-cell encounter is due to activation of the survival IκBα/ERK/WWOX signaling. Mechanistically, cell surface epitope WWOX286-299 (repl) in WWOXf repels the invading WWOXd to undergo retrograde migration. However, when epitope WWOX7-21 (gre) is exposed, WWOXf greets WWOXd to migrate forward for merge. WWOX binds membrane type II TGFβ receptor (TβRII), and TβRII IgG-pretreated WWOXf greet WWOXd to migrate forward and merge with each other. In contrast, TβRII IgG-pretreated WWOXd loses recognition by WWOXf, and WWOXf mediates apoptosis of WWOXd. The observatons suggest that normal cells can be activated to attack metastatic cancer cells. WWOXd cells are less efficient in generating Ca2+ influx and undergo non-apoptotic explosion in response to UV irradiation in room temperature. WWOXf cells exhibit bubbling cell death and Ca2+ influx effectively caused by UV or apoptotic stress. Together, membrane WWOX/TβRII complex is needed for cell-to-cell recognition, maintaining the efficacy of Ca2+ influx, and control of cell invasiveness.

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TAMI-57. MEDULLOBLASTOMA UTILIZE GABA TRANSAMINASE TO SURVIVE IN THE CEREBROSPINAL FLUID MICROENVIRONMENT AND PROMOTE LEPTOMENINGEAL DISSEMINATION

Neuro-Oncology ◽

10.1093/neuonc/noaa215.944 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii225-ii226

Author(s):

Vahan Martirosian ◽

Krutika Deshpande ◽

Hao Zhou ◽

Keyue Shen ◽

Vazgen Stepanosyan ◽

...

Keyword(s):

Energy Source ◽

Cerebrospinal Fluid ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Metastatic Cancer ◽

Leptomeningeal Metastases ◽

Metabolic Phenotype ◽

Leptomeningeal Disease ◽

Neural Cells ◽

Gaba Transaminase

Abstract Medulloblastoma (MB) is a malignant pediatric brain tumor. Studies have shown heterogeneous cells amongst the tumor bulk which mirror normal neural cells in various neurodevelopmental stages. To discern exploited mechanisms promoting MB leptomeningeal disease, we drew conclusions from developmental neurobiology. In normal differentiation, the metabolic phenotype in proliferating neural progenitor cells evolves from a glycolysis-dependent to an oxidative phosphorylation-reliant energetic profile in quiescent differentiated neurons. Cancer cells mirror this evolution, which also grants them the capability to utilize alternative nutrients in the microenvironment as an energy source. Considering metastatic cells are typically in a dormant state and primarily utilize oxidative phosphorylation, we hypothesized metastatic MB cells emulate a quiescent neuron-like cellular profile to survive in the cerebrospinal fluid and form leptomeningeal metastases. To examine this, we query the expression of GABA catabolic enzyme GABA transaminase (ABAT) in MB. GABA is found in the cerebellar and leptomeningeal microenvironments, and is utilized by metastatic cancer cells in the CNS as an energy source. We correlate an increase in ABAT expression with neurodevelopment and show heterogeneous expression of this protein in primary MB tumors. MB cells with increased expression of ABAT were slower-dividing, expressed a genetic and metabolic phenotype reminiscent of quiescent neuron-like cells, and had increased capability to metabolize GABA. Conversely, lower expression of ABAT was associated with an increased proliferation rate and correlated with a progenitor-like cellular profile. Transplantation of MB cells into the leptomeningeal compartment decreased proliferative capacity and enhanced ABAT expression. Xenograft models showed MB cells with ABAT knockdown had increased growth in the cerebellar microenvironment. Conversely, MB cells with ABAT overexpression transplanted into the cerebrospinal fluid formed leptomeningeal metastases whereas ABAT knockdown cells could not. These results suggest ABAT expression in MB cells can be modulated by the tumor microenvironment and is required to form leptomeningeal metastases.

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Fer and FerT Govern Mitochondrial Susceptibility to Metformin and Hypoxic Stress in Colon and Lung Carcinoma Cells

Cells ◽

10.3390/cells10010097 ◽

2021 ◽

Vol 10 (1) ◽

pp. 97

Author(s):

Odeya Marciano ◽

Linoy Mehazri ◽

Sally Shpungin ◽

Alexander Varvak ◽

Eldad Zacksenhaus ◽

...

Keyword(s):

Cancer Cells ◽

Aerobic Glycolysis ◽

Metastatic Cancer ◽

Carcinoma Cells ◽

Metabolic Adaptation ◽

Hypoxic Stress ◽

Lung Carcinoma Cells ◽

Metabolic Role ◽

Highly Sensitive ◽

Anticancer Treatment

Aerobic glycolysis is an important metabolic adaptation of cancer cells. However, there is growing evidence that reprogrammed mitochondria also play an important metabolic role in metastatic dissemination. Two constituents of the reprogrammed mitochondria of cancer cells are the intracellular tyrosine kinase Fer and its cancer- and sperm-specific variant, FerT. Here, we show that Fer and FerT control mitochondrial susceptibility to therapeutic and hypoxic stress in metastatic colon (SW620) and non-small cell lung cancer (NSCLC-H1299) cells. Fer- and FerT-deficient SW620 and H1299 cells (SW∆Fer/FerT and H∆Fer/FerT cells, respectively) become highly sensitive to metformin treatment and to hypoxia under glucose-restrictive conditions. Metformin impaired mitochondrial functioning that was accompanied by ATP deficiency and robust death in SW∆Fer/FerT and H∆Fer/FerT cells compared to the parental SW620 and H1299 cells. Notably, selective knockout of the fer gene without affecting FerT expression reduced sensitivity to metformin and hypoxia seen in SW∆Fer/FerT cells. Thus, Fer and FerT modulate the mitochondrial susceptibility of metastatic cancer cells to hypoxia and metformin. Targeting Fer/FerT may therefore provide a novel anticancer treatment by efficient, selective, and more versatile disruption of mitochondrial function in malignant cells.

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Transcriptional landscape of cellular networks reveal interactions driving the dormancy mechanisms in cancer

Scientific Reports ◽

10.1038/s41598-021-94005-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Dilara Uzuner ◽

Yunus Akkoç ◽

Nesibe Peker ◽

Pınar Pir ◽

Devrim Gözüaçık ◽

...

Keyword(s):

Cancer Cells ◽

Regulatory Networks ◽

Metastatic Cancer ◽

Interaction Network ◽

Current Treatment ◽

Cellular Mechanisms ◽

Protein Protein Interaction ◽

Cancer Dormancy ◽

Protein Protein Interaction Networks ◽

First Time

AbstractPrimary cancer cells exert unique capacity to disseminate and nestle in distant organs. Once seeded in secondary sites, cancer cells may enter a dormant state, becoming resistant to current treatment approaches, and they remain silent until they reactivate and cause overt metastases. To illuminate the complex mechanisms of cancer dormancy, 10 transcriptomic datasets from the literature enabling 21 dormancy–cancer comparisons were mapped on protein–protein interaction networks and gene-regulatory networks to extract subnetworks that are enriched in significantly deregulated genes. The genes appearing in the subnetworks and significantly upregulated in dormancy with respect to proliferative state were scored and filtered across all comparisons, leading to a dormancy–interaction network for the first time in the literature, which includes 139 genes and 1974 interactions. The dormancy interaction network will contribute to the elucidation of cellular mechanisms orchestrating cancer dormancy, paving the way for improvements in the diagnosis and treatment of metastatic cancer.

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Context-Specific Efficacy of Apalutamide Therapy in Preclinical Models of Pten-Deficient Prostate Cancer

Cancers ◽

10.3390/cancers13163975 ◽

2021 ◽

Vol 13 (16) ◽

pp. 3975

Author(s):

Marco A. De Velasco ◽

Yurie Kura ◽

Naomi Ando ◽

Noriko Sako ◽

Eri Banno ◽

...

Keyword(s):

Prostate Cancer ◽

Antitumor Activity ◽

Cancer Cells ◽

Late Stage ◽

Early Stage ◽

Castration Resistant Prostate Cancer ◽

Akt Inhibitor ◽

Molecular Features ◽

Context Specific

Significant improvements with apalutamide, a nonsteroidal antiandrogen used to treat patients suffering from advanced prostate cancer (PCa), have prompted evaluation for additional indications and therapeutic development with other agents; however, persistent androgen receptor (AR) signaling remains problematic. We used autochthonous mouse models of Pten-deficient PCa to examine the context-specific antitumor activity of apalutamide and profile its molecular responses. Overall, apalutamide showed potent antitumor activity in both early-stage and late-stage models of castration-naïve prostate cancer (CNPC). Molecular profiling by Western blot and immunohistochemistry associated persistent surviving cancer cells with upregulated AKT signaling. While apalutamide was ineffective in an early-stage model of castration-resistant prostate cancer (CRPC), it tended to prolong survival in late-stage CRPC. Molecular features associated with surviving cancer cells in CRPC included upregulated aberrant-AR, and phosphorylated S6 and proline-rich Akt substrate of 40 kDa (PRAS40). Strong synergy was observed with the pan-AKT inhibitor GSK690693 and apalutamide in vitro against the CNPC- and CRPC-derived cell lines and tended to improve the antitumor responses in CNPC but not CRPC in vivo. Upregulation of signal transducer and activator of transcription 3 (STAT3) and proviral insertion in murine-1 (PIM-1) were associated with combined apalutamide/GSK690693. Our findings show that apalutamide can attenuate Pten-deficient PCa in a context-specific manner and provides data that can be used to further study and, possibly, develop additional combinations with apalutamide.

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Light- and Melanin Nanoparticle-Induced Cytotoxicity in Metastatic Cancer Cells

Pharmaceutics ◽

10.3390/pharmaceutics13070965 ◽

2021 ◽

Vol 13 (7) ◽

pp. 965

Author(s):

Victoria R. Gabriele ◽

Robabeh M. Mazhabi ◽

Natalie Alexander ◽

Purna Mukherjee ◽

Thomas N. Seyfried ◽

...

Keyword(s):

Cancer Cells ◽

Metastatic Cancer ◽

Energy Levels ◽

Nanoparticle Concentration ◽

Visible Radiation ◽

Laser Illumination ◽

Wide Range ◽

Low Glucose ◽

Melanin Nanoparticles ◽

Metastatic Cancer Cells

Melanin nanoparticles are known to be biologically benign to human cells for a wide range of concentrations in a high glucose culture nutrition. Here, we show cytotoxic behavior at high nanoparticle and low glucose concentrations, as well as at low nanoparticle concentration under exposure to (nonionizing) visible radiation. To study these effects in detail, we developed highly monodispersed melanin nanoparticles (both uncoated and glucose-coated). In order to study the effect of significant cellular uptake of these nanoparticles, we employed three cancer cell lines: VM-M3, A375 (derived from melanoma), and HeLa, all known to exhibit strong macrophagic character, i.e., strong nanoparticle uptake through phagocytic ingestion. Our main observations are: (i) metastatic VM-M3 cancer cells massively ingest melanin nanoparticles (mNPs); (ii) the observed ingestion is enhanced by coating mNPs with glucose; (iii) after a certain level of mNP ingestion, the metastatic cancer cells studied here are observed to die—glucose coating appears to slow that process; (iv) cells that accumulate mNPs are much more susceptible to killing by laser illumination than cells that do not accumulate mNPs; and (v) non-metastatic VM-NM1 cancer cells also studied in this work do not ingest the mNPs, and remain unaffected after receiving identical optical energy levels and doses. Results of this study could lead to the development of a therapy for control of metastatic stages of cancer.

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Reduced Lamin A/C does Not Facilitate Cancer Cell Transendothelial Migration but Compromises Lung Metastasis

Cancers ◽

10.3390/cancers13102383 ◽

2021 ◽

Vol 13 (10) ◽

pp. 2383

Author(s):

Francesco Roncato ◽

Ofer Regev ◽

Sara W. Feigelson ◽

Sandeep Kumar Yadav ◽

Lukasz Kaczmarczyk ◽

...

Keyword(s):

Cancer Cells ◽

Lung Metastasis ◽

Metastatic Cancer ◽

Nuclear Lamina ◽

Transendothelial Migration ◽

Soft Agar ◽

Lamin A ◽

And Migration

The mechanisms by which the nuclear lamina of tumor cells influences tumor growth and migration are highly disputed. Lamin A and its variant lamin C are key lamina proteins that control nucleus stiffness and chromatin conformation. Downregulation of lamin A/C in two prototypic metastatic lines, B16F10 melanoma and E0771 breast carcinoma, facilitated cell squeezing through rigid pores, and reduced heterochromatin content. Surprisingly, both lamin A/C knockdown cells grew poorly in 3D spheroids within soft agar, and lamin A/C deficient cells derived from spheroids transcribed lower levels of the growth regulator Yap1. Unexpectedly, the transendothelial migration of both cancer cells in vitro and in vivo, through lung capillaries, was not elevated by lamin A/C knockdown and their metastasis in lungs was even dramatically reduced. Our results are the first indication that reduced lamin A/C content in distinct types of highly metastatic cancer cells does not elevate their transendothelial migration (TEM) capacity and diapedesis through lung vessels but can compromise lung metastasis at a post extravasation level.

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The In Vivo Selection Method in Breast Cancer Metastasis

International Journal of Molecular Sciences ◽

10.3390/ijms22041886 ◽

2021 ◽

Vol 22 (4) ◽

pp. 1886

Author(s):

Jun Nakayama ◽

Yuxuan Han ◽

Yuka Kuroiwa ◽

Kazushi Azuma ◽

Yusuke Yamamoto ◽

...

Keyword(s):

Cancer Cells ◽

Cell Lines ◽

Cancer Metastasis ◽

Metastatic Cancer ◽

Expression Patterns ◽

Selection Method ◽

Gene Signatures ◽

In Vivo Selection ◽

Metastatic Cancer Cells

Metastasis is a complex event in cancer progression and causes most deaths from cancer. Repeated transplantation of metastatic cancer cells derived from transplanted murine organs can be used to select the population of highly metastatic cancer cells; this method is called as in vivo selection. The in vivo selection method and highly metastatic cancer cell lines have contributed to reveal the molecular mechanisms of cancer metastasis. Here, we present an overview of the methodology for the in vivo selection method. Recent comparative analysis of the transplantation methods for metastasis have revealed the divergence of metastasis gene signatures. Even cancer cells that metastasize to the same organ show various metastatic cascades and gene expression patterns by changing the transplantation method for the in vivo selection. These findings suggest that the selection of metastasis models for the study of metastasis gene signatures has the potential to influence research results. The study of novel gene signatures that are identified from novel highly metastatic cell lines and patient-derived xenografts (PDXs) will be helpful for understanding the novel mechanisms of metastasis.

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