scholarly journals RAC1 Activation as a Potential Therapeutic Option in Metastatic Cutaneous Melanoma

Biomolecules ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 1554
Author(s):  
Paula Colón-Bolea ◽  
Rocío García-Gómez ◽  
Berta Casar
Keyword(s):  
Cutaneous Melanoma ◽  
Therapeutic Option ◽  
Metastatic Potential ◽  
Surface Receptors ◽  
Cancer Migration ◽  
Complex Process ◽  
Rho Family ◽  
Signaling Activation ◽  
Melanoma Therapy

Metastasis is a complex process by which cancer cells escape from the primary tumor to colonize distant organs. RAC1 is a member of the RHO family of small guanosine triphosphatases that plays an important role in cancer migration, invasion, angiogenesis and metastasis. RAC1 activation has been related to most cancers, such as cutaneous melanoma, breast, lung, and pancreatic cancer. RAC1P29S driver mutation appears in a significant number of cutaneous melanoma cases. Likewise, RAC1 is overexpressed or hyperactivated via signaling through oncogenic cell surface receptors. Thus, targeting RAC1 represents a promising strategy for cutaneous melanoma therapy, as well as for inhibition of other signaling activation that promotes resistance to targeted therapies. In this review, we focus on the role of RAC1 in metastatic cutaneous melanoma emphasizing the anti-metastatic potential of RAC1- targeting drugs.

scholarly journals Chemokine Pathways in Cutaneous Melanoma: Their Modulation by Cancer and Exploitation by the Clinician

Cancers ◽  
2021 ◽  
Vol 13 (22) ◽  
pp. 5625
Author(s):  
Rebecca Adams ◽  
Bernhard Moser ◽  
Sophia N. Karagiannis ◽  
Katie E. Lacy
Keyword(s):  
Immune Cells ◽  
Cutaneous Melanoma ◽  
Epithelial To Mesenchymal Transition ◽  
Immune Cell ◽  
Metastatic Potential ◽  
Mesenchymal Transition ◽  
Emerging Therapies ◽  
Dense Cell ◽  
Chemokine Signalling ◽  
Melanoma Therapy

The incidence of cutaneous malignant melanoma is rising globally and is projected to continue to rise. Advances in immunotherapy over the last decade have demonstrated that manipulation of the immune cell compartment of tumours is a valuable weapon in the arsenal against cancer; however, limitations to treatment still exist. Cutaneous melanoma lesions feature a dense cell infiltrate, coordinated by chemokines, which control the positioning of all immune cells. Melanomas are able to use chemokine pathways to preferentially recruit cells, which aid their growth, survival, invasion and metastasis, and which enhance their ability to evade anticancer immune responses. Aside from this, chemokine signalling can directly influence angiogenesis, invasion, lymph node, and distal metastases, including epithelial to mesenchymal transition-like processes and transendothelial migration. Understanding the interplay of chemokines, cancer cells, and immune cells may uncover future avenues for melanoma therapy, namely: identifying biomarkers for patient stratification, augmenting the effect of current and emerging therapies, and designing specific treatments to target chemokine pathways, with the aim to reduce melanoma pathogenicity, metastatic potential, and enhance immune cell-mediated cancer killing. The chemokine network may provide selective and specific targets that, if included in current therapeutic regimens, harbour potential to improve outcomes for patients.

scholarly journals Immune Profile Of Uveal Melanoma Patients: Impact On Clinical Outcome

2021 ◽  
Author(s):  
Ernesto Rossi ◽  
Ilaria Grazia Zizzari ◽  
Alessandra Di Filippo ◽  
Anna Acampora ◽  
Monica Maria Pagliara ◽  
...  
Keyword(s):  
Uveal Melanoma ◽  
Immune Checkpoint ◽  
Cutaneous Melanoma ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Therapeutic Option ◽  
Immune Profile ◽  
Melanoma Patients ◽  
Low Activity

Abstract Background. Immunotherapy represents a common therapeutic option for metastatic uveal melanoma, despite the low activity. Although overall survival is often dismal, long survivors can be observed. In this study, the prognostic role of the soluble isoforms of immunomodulatory receptors and cytokines/chemokines was evaluated as well as their ability to identify patients who can benefit more from anti-PD-1 therapy. Methods. Sera from 22 metastatic uveal melanoma patients were assayed to evaluate the levels of cytokines/chemokines and soluble immune checkpoint molecules by multiplex immunoassay analysis. The changes of these molecules during anti-PD-1 therapy were assessed. The correlation between soluble isoforms of immunomodulatory receptors/cytokines/chemokines and survival was analysed. A comparison between circulating immune profile of metastatic uveal melanoma and cutaneous melanoma during anti-PD-1 therapy was also performed. Results. The levels of sCD137, sCD28, sPD-1, sPD-L2 sLAG3, sCD80 and sTim3 were significantly enhanced during anti-PD-1 treatment. Similarly, the levels of IP-10, CCL2 and IDO activity were significantly increased during anti-PD-1 therapy. HVEM, IL-8 and IDO activity were higher in patients with survival < 6 months. Considering these 3 molecules, we obtained a score able to predict patients’ survival. Serum CD137, sGITR and sCD27 were significantly lower in patients with survival > 30 months. Serum GITR, sCD27, sPD-1, sCD80, IFNγ and IDO activity were significantly higher in uveal melanoma patients than in cutaneous melanoma patients during anti-PD-1 therapy. Conclusions. The molecules detected in uveal melanoma during anti-PD-1 treatment reflect the poor activation of immune system and may justify the limited response to immune checkpoint inhibitors. Nevertheless, some patients with metastatic uveal melanoma had a long survival. These patients could be identified through a score based on circulating immune molecules such as HVEM, IDO and IL-8. The comparison of immune profile during anti-PD-1 therapy between uveal melanoma and cutaneous melanoma reflects the different efficacy of immune checkpoint inhibitors in these diseases.

scholarly journals Autophagy- An emerging target for melanoma therapy

F1000Research ◽  
2016 ◽  
Vol 5 ◽  
pp. 1888 ◽  
Author(s):  
Abibatou Ndoye ◽  
Ashani T. Weeraratna
Keyword(s):  
Metabolic Stress ◽  
Metastatic Potential ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Cancer Death ◽  
Drug Induced ◽  
Resistance To Therapy ◽  
Advanced Stages ◽  
Melanoma Therapy

Melanoma accounts for only 5% of all cancers but is the leading cause of skin cancer death due to its high metastatic potential. Patients with metastatic melanoma have a 10-year survival rate of less than 10%. While the clinical landscape for melanoma is evolving rapidly, lack of response to therapies, as well as resistance to therapy remain critical obstacles for treatment of this disease. In recent years, a myriad of therapy resistance mechanisms have been unravelled, one of which is autophagy, the focus of this review. In advanced stages of malignancy, melanoma cells hijack the autophagy machinery in order to alleviate drug-induced and metabolic stress in the tumor microenvironment, thereby promoting resistance to multiple therapies, tumor cell survival, and progression.  Autophagy is an essential cellular process that maintains cellular homeostasis through the recycling of intracellular constituents. Early studies on the role of autophagy in cancer generated controversy as to whether autophagy was pro- or anti-tumorigenic. Currently, there is a consensus that autophagy is tumor-suppressive in the early stages of cancer and tumor-promoting in established tumors.  This review aims to highlight current understandings on the role of autophagy in melanoma malignancy, and specifically therapy resistance; as well as to evaluate recent strategies for therapeutic autophagy modulation.

Extracellular matrix: the gatekeeper of tumor angiogenesis

2019 ◽  
Vol 47 (5) ◽  
pp. 1543-1555 ◽  
Author(s):  
Maurizio Mongiat ◽  
Simone Buraschi ◽  
Eva Andreuzzi ◽  
Thomas Neill ◽  
Renato V. Iozzo
Keyword(s):  
Extracellular Matrix ◽  
Tumor Angiogenesis ◽  
Signaling Cascades ◽  
Cancer Growth ◽  
Cell Behavior ◽  
Metastatic Progression ◽  
Surface Receptors ◽  
The Matrix ◽  
Multiple Signaling

Abstract The extracellular matrix is a network of secreted macromolecules that provides a harmonious meshwork for the growth and homeostatic development of organisms. It conveys multiple signaling cascades affecting specific surface receptors that impact cell behavior. During cancer growth, this bioactive meshwork is remodeled and enriched in newly formed blood vessels, which provide nutrients and oxygen to the growing tumor cells. Remodeling of the tumor microenvironment leads to the formation of bioactive fragments that may have a distinct function from their parent molecules, and the balance among these factors directly influence cell viability and metastatic progression. Indeed, the matrix acts as a gatekeeper by regulating the access of cancer cells to nutrients. Here, we will critically evaluate the role of selected matrix constituents in regulating tumor angiogenesis and provide up-to-date information concerning their primary mechanisms of action.

The role of Rho-family GTPases in human glioblastomas

2004 ◽  
Vol 31 (S 1) ◽  
Author(s):  
S Seta ◽  
M Herr ◽  
S Horn ◽  
D Koch ◽  
T Vogt ◽  
...  
Keyword(s):  
Rho Family Gtpases ◽  
Rho Family

Vitamin D as potential therapeutic anticancer agent

2018 ◽  
pp. 1-3
Keyword(s):  
Vitamin D ◽  
Anticancer Activity ◽  
Anticancer Agent ◽  
Antitumor Agents ◽  
Metastatic Potential ◽  
Anticancer Properties ◽  
Chemotherapy Agents

The role of vitamin D is implicated in carcinogenesis through numerous biological processes like induction of apoptosis, modulation of immune system inhibition of inflammation and cell proliferation and promotion of cell differentiation. Its use as additional adjuvant drug with cancer treatment may be novel combination for improved outcome of different cancers. Numerous preclinical, epidemiological and clinical studies support the role of vitamin D as an anticancer agent. Anticancer properties of vitamin D have been studied widely (both in vivo and in vitro) among various cancers and found to have promising results. There are considerable data that indicate synergistic potential of calcitriol and antitumor agents. Possible mechanisms for modulatory anticancer activity of vitamin D include its antiproliferative, prodifferentiating, and anti-angiogenic and apoptic properties. Calcitriol reduces invasiveness and metastatic potential of many cancer cells by inhibiting angiogenesis and regulating expression of the key molecules involved in invasion and metastasis. Anticancer activity of vitamin D is synergistic or additive with the antineoplastic actions of several drugs including cytotoxic chemotherapy agents like paclitaxel, docetaxel, platinum base compounds and mitoxantrone. Benefits of addition of vitamin D should be weighed against the risk of its toxicity.

Social Cohesion, Breaks, and Transformations in Italy, 535–600

2018 ◽  
Author(s):  
Walter Pohl
Keyword(s):  
The Political ◽  
Late Antique ◽  
Religious Context ◽  
Ancient Society ◽  
Complex Process ◽  
Term Change ◽  
Two Generations ◽  
Classical Culture

When the Gothic War began in Italy in 535, the country still conserved many features of classical culture and late antique administration. Much of that was lost in the political upheavals of the following decades. Building on Chris Wickham’s work, this contribution sketches an integrated perspective of these changes, attempting to relate the contingency of events to the logic of long-term change, discussing political options in relation to military and economic means, and asking in what ways the erosion of consensus may be understood in a cultural and religious context. What was the role of military entrepreneurs of more or less barbarian or Roman extraction in the distribution or destruction of resources? How did Christianity contribute to the transformation of ancient society? The old model of barbarian invasions can contribute little to understanding this complex process. It is remarkable that for two generations, all political strategies in Italy ultimately failed.

Open Treatment of Osteochondral Lesions of the Talus With Bone Grafting and Particulated Juvenile Cartilage Allografting

2021 ◽  
pp. 193864002110097
Author(s):  
Suhas P. Dasari ◽  
Thomas M. Langer ◽  
Derek Parshall ◽  
Brian Law
Keyword(s):  
Therapeutic Option ◽  
Symptomatic Improvement ◽  
Pain Scale ◽  
Osteochondral Lesions ◽  
Outcome Scores ◽  
Scale Scores ◽  
Open Treatment ◽  
Bone Autograft

Background: Large cystic osteochondral lesions of the talus (OLT) are challenging pathological conditions to treat, but particulated juvenile cartilage allografts (PJCAs) supplemented with bone grafts are a promising therapeutic option. The purpose of this project was to further elucidate the role of PJCA with concomitant bone autografts for treating large cystic OLTs with extensive subchondral bone involvement (greater than 150 mm2 in area and/or deeper than 5 mm). Methods: We identified 6 patients with a mean OLT area of 307.2 ± 252.4 mm2 and a mean lesion depth of 10.85 ± 6.10 mm who underwent DeNovo PJCA with bone autografting between 2013 and 2017. Postoperative outcomes were assessed with radiographs, Foot and Ankle Outcome Scores (FAOS), and visual pain scale scores. Results: At final follow-up (27.0 ± 12.59 weeks), all patients had symptomatic improvement and incorporation of the graft on radiographs. At an average of 62 ± 20.88 months postoperatively, no patients required a revision surgery. All patients contacted by phone in 2018 and 2020 reported they would do the procedure again in retrospect and reported an improvement in their symptoms relative to their preoperative state, especially with pain and in the FAOS activities of daily living subsection (91.93 ± 9.04 in 2018, 74.63 ± 26.86 in 2020). Conclusion: PJCA with concomitant bone autograft is a viable treatment option for patients with large cystic OLTs. Levels of Evidence: Level IV

The Need for Consensus About Liver Transplantation For Patients With Neuropsychiatric Wilson’s Disease

2021 ◽  
pp. 152692482110028
Author(s):  
Alberto Ferrarese ◽  
Patrizia Burra
Keyword(s):  
Liver Transplantation ◽  
Patient Outcomes ◽  
Wilson’S Disease ◽  
Therapeutic Option ◽  
Copper Metabolism ◽  
Wilson's Disease ◽  
Published Data ◽  
Neurological Improvement ◽  
Effective Therapeutic Option

Liver transplantation is considered an effective therapeutic option for Wilson’s disease (WD) patients with hepatic phenotype, since it removes the inherited defects of copper metabolism, and is associated with excellent graft and patient outcomes. The role of liver transplantation in WD patients with mixed hepatic and neuropsychiatric phenotype has remained controversial over time, mainly because of high post-operative complications, reduced survival and a variable, unpredictable rate of neurological improvement. This article critically discusses the recently published data in this field, focussing in more detail on isolated neuropsychiatric phenotype as a potential indication for liver transplantation in WD patients.

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