International Journal of Molecular Sciences

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21 pages, 2846 KiB

Open AccessArticle

Single-Domain Antibodies Represent Novel Alternatives to Monoclonal Antibodies as Targeting Agents against the Human Papillomavirus 16 E6 Protein

by Melissa Togtema, Greg Hussack, Guillem Dayer, Megan R. Teghtmeyer, Shalini Raphael, Jamshid Tanha and Ingeborg Zehbe

Int. J. Mol. Sci. 2019, 20(9), 2088; https://doi.org/10.3390/ijms20092088 - 28 Apr 2019

Cited by 10 | Viewed by 4864

Abstract

Approximately one fifth of all malignancies worldwide are etiologically associated with a persistent viral or bacterial infection. Thus, there is a particular interest in therapeutic molecules which use components of a natural immune response to specifically inhibit oncogenic microbial proteins, as it is [...] Read more.

Approximately one fifth of all malignancies worldwide are etiologically associated with a persistent viral or bacterial infection. Thus, there is a particular interest in therapeutic molecules which use components of a natural immune response to specifically inhibit oncogenic microbial proteins, as it is anticipated they will elicit fewer off-target effects than conventional treatments. This concept has been explored in the context of human papillomavirus 16 (HPV16)-related cancers, through the development of monoclonal antibodies and fragments thereof against the viral E6 oncoprotein. Challenges related to the biology of E6 as well as the functional properties of the antibodies themselves appear to have precluded their clinical translation. Here, we addressed these issues by exploring the utility of the variable domains of camelid heavy-chain-only antibodies (denoted as VHHs). Through construction and panning of two llama, immune VHH phage display libraries, a pool of potential VHHs was isolated. The interactions of these with recombinant E6 were further characterized using an enzyme-linked immunosorbent assay (ELISA), Western blotting under denaturing and native conditions, and surface plasmon resonance. Three VHHs were identified that bound recombinant E6 with nanomolar affinities. Our results lead the way for subsequent studies into the ability of these novel molecules to inhibit HPV16-infected cells in vitro and in vivo. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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14 pages, 2110 KiB

Open AccessArticle

Potential Interplay of the Gatipotuzumab Epitope TA-MUC1 and Estrogen Receptors in Ovarian Cancer

by Sabine Heublein, Sabina Page, Doris Mayr, Elisa Schmoeckel, Fabian Trillsch, Frederik Marmé, Sven Mahner, Udo Jeschke and Aurelia Vattai

Int. J. Mol. Sci. 2019, 20(2), 295; https://doi.org/10.3390/ijms20020295 - 12 Jan 2019

Cited by 8 | Viewed by 4437

Abstract

Anti-tumor efficacy of Gatipotuzumab, a therapeutic antibody targeting Tumor-Associated Mucin-1 (TA-MUC1), in relapsed ovarian cancer (OC) appeared to be rather heterogeneous. Whether adding a second anti-neoplastic drug may augment response towards Gatipotuzumab, has not been elucidated so far. Since it is known that [...] Read more.

Anti-tumor efficacy of Gatipotuzumab, a therapeutic antibody targeting Tumor-Associated Mucin-1 (TA-MUC1), in relapsed ovarian cancer (OC) appeared to be rather heterogeneous. Whether adding a second anti-neoplastic drug may augment response towards Gatipotuzumab, has not been elucidated so far. Since it is known that anti-MUC1 antibodies may alter estrogen receptor activity in breast cancer, this potential interplay was investigated in OC. The correlation between TA-MUC1, estrogen receptors (ERs) and another 12 protein markers as well as their correlation with clinico-pathological parameters in 138 ovarian cancer cases was studied. Finally, Gatipotuzumab and 4-Hydroxy-TTamoxifen (4-OHT) as well as the combination of both was tested for its impact on cell viability in COV318, OV-90, OVCAR-3, and SKOV-3 cells. A strong positive correlation between TA-MUC1 and ERs was detected in OC tissue. Those cases missing ERs but staining positive for TA-MUC1 had significantly reduced overall survival. The combination of 4-OHT and Gatipotuzumab significantly reduced cell viability and was more effective than treatment with Gatipotuzumab alone. Co-stimulation with Gatipotuzumab enhanced the efficacy of 4-OHT in OVCAR-3 and SKOV-3. The data suggest an interplay of TA-MUC1 and ERs in OC. Whether the combination of Gatipotuzumab and TTamoxifen may enhance efficacy of either of the two drugs in vivo, or may even translate into a clinically relevant benefit over the respective monotherapies, remains to be investigated. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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10 pages, 4039 KiB

Open AccessArticle

The Epithelial-Mesenchymal Transition Initiated by Malignant Ascites Underlies the Transmesothelial Invasion of Ovarian Cancer Cells

by Martyna Pakuła, Justyna Mikuła-Pietrasik, Anna Witucka, Katarzyna Kostka-Jeziorny, Paweł Uruski, Rafał Moszyński, Eryk Naumowicz, Stefan Sajdak, Andrzej Tykarski and Krzysztof Książek

Int. J. Mol. Sci. 2019, 20(1), 137; https://doi.org/10.3390/ijms20010137 - 2 Jan 2019

Cited by 14 | Viewed by 3911

Abstract

The role of the epithelial-mesenchymal transition (EMT) in ovarian cancer cell progression is unquestioned. In this report, we describe that malignant ascites, fluid that accumulates in the peritoneal cavity in a large group of patients with ovarian cancer, stimulate EMT in two representative [...] Read more.

The role of the epithelial-mesenchymal transition (EMT) in ovarian cancer cell progression is unquestioned. In this report, we describe that malignant ascites, fluid that accumulates in the peritoneal cavity in a large group of patients with ovarian cancer, stimulate EMT in two representative ovarian cancer cell lines (A2780, SKOV-3). In addition, we identify the ascites-derived mediators of EMT and signaling pathways initiated in the cancer cells that underlie this phenomenon. Finally, we demonstrate that EMT induced in the cancer cells in response to the malignant ascites contributes to their increased transmesothelial invasion. Altogether, our study provides new insight into the mechanistic aspects of the malignant ascites-dependent exacerbation of the intraperitoneal progression of ovarian cancer. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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21 pages, 4157 KiB

Open AccessArticle

Key Immunological Functions Involved in the Progression of Epithelial Ovarian Serous Carcinoma Discovered by the Gene Ontology-Based Immunofunctionome Analysis

by Cheng-Chang Chang, Kuo-Min Su, Kai-Hsi Lu, Chi-Kang Lin, Peng-Hui Wang, Hsin-Yang Li, Mong-Lien Wang, Cheng-Kuo Lin, Mu-Hsien Yu and Chia-Ming Chang

Int. J. Mol. Sci. 2018, 19(11), 3311; https://doi.org/10.3390/ijms19113311 - 24 Oct 2018

Cited by 14 | Viewed by 3085

Abstract

Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well as their change during the progression of SC have not been investigated in [...] Read more.

Serous carcinoma (SC) is the most common and lethal subtype of epithelial ovarian carcinoma; immunotherapy is a potential treatment for SC, however, the global immunological functions of SC as well as their change during the progression of SC have not been investigated in detail till now. We conducted a genome-wide integrative analysis to investigate the immunofunctionomes of SC at four tumor stages by quantifying the immunological functions defined by the Gene Ontology gene sets. DNA microarray gene expression profiles of 1100 SCs and 136 normal ovarian tissue controls were downloaded from the Gene Expression Omnibus database and converted to the functionome. Then the immunofunctionomes were reconstructed by extracting the offspring from the functionome for the four SC staging groups. The key immunological functions extracted from immunofunctionomes with a series of filters revealed that the immunopathy of SC consisted of a group of deregulated functions with the core members including B cell activation and differentiation, regulation of leukocyte chemotaxis/cellular extravasation, antigen receptor mediated signaling pathway, T helper mediated immunity and macrophage activation; and the auxiliary elements included leukocyte mediated immunity, regulation of inflammatory response, T cell differentiation, mononuclear cell migration, megakaryocyte differentiation, complement activation and cytokine production. These deregulated immunological functions reveal the candidates to target in the immunotherapy. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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Review

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17 pages, 926 KiB

Open AccessReview

Therapeutic Targeting of Collective Invasion in Ovarian Cancer

by Laura Moffitt, Nazanin Karimnia, Andrew Stephens and Maree Bilandzic

Int. J. Mol. Sci. 2019, 20(6), 1466; https://doi.org/10.3390/ijms20061466 - 22 Mar 2019

Cited by 49 | Viewed by 8007

Abstract

Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. [...] Read more.

Ovarian cancer is the seventh most commonly diagnosed cancer amongst women and has the highest mortality rate of all gynaecological malignancies. It is a heterogeneous disease attributed to one of three cell types found within the reproductive milieu: epithelial, stromal, and germ cell. Each histotype differs in etiology, pathogenesis, molecular biology, risk factors, and prognosis. Furthermore, the origin of ovarian cancer remains unclear, with ovarian involvement secondary to the contribution of other gynaecological tissues. Despite these complexities, the disease is often treated as a single entity, resulting in minimal improvement to survival rates since the introduction of platinum-based chemotherapy over 30 years ago. Despite concerted research efforts, ovarian cancer remains one of the most difficult cancers to detect and treat, which is in part due to the unique mode of its dissemination. Ovarian cancers tend to invade locally to neighbouring tissues by direct extension from the primary tumour, and passively to pelvic and distal organs within the peritoneal fluid or ascites as multicellular spheroids. Once at their target tissue, ovarian cancers, like most epithelial cancers including colorectal, melanoma, and breast, tend to invade as a cohesive unit in a process termed collective invasion, driven by specialized cells termed “leader cells”. Emerging evidence implicates leader cells as essential drivers of collective invasion and metastasis, identifying collective invasion and leader cells as a viable target for the management of metastatic disease. However, the development of targeted therapies specifically against this process and this subset of cells is lacking. Here, we review our understanding of metastasis, collective invasion, and the role of leader cells in ovarian cancer. We will discuss emerging research into the development of novel therapies targeting collective invasion and the leader cell population. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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13 pages, 239 KiB

Open AccessReview

Strengthening the AntiTumor NK Cell Function for the Treatment of Ovarian Cancer

by Marco Greppi, Giovanna Tabellini, Ornella Patrizi, Simona Candiani, Andrea Decensi, Silvia Parolini, Simona Sivori, Silvia Pesce, Laura Paleari and Emanuela Marcenaro

Int. J. Mol. Sci. 2019, 20(4), 890; https://doi.org/10.3390/ijms20040890 - 19 Feb 2019

Cited by 31 | Viewed by 5410

Abstract

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment [...] Read more.

The crosstalk between cancer cells and host cells is a crucial prerequisite for tumor growth and progression. The cells from both the innate and adaptive immune systems enter into a perverse relationship with tumor cells to create a tumor-promoting and immunosuppressive tumor microenvironment (TME). Epithelial ovarian cancer (EOC), the most lethal of all gynecological malignancies, is characterized by a unique TME that paves the way to the formation of metastasis and mediates therapy resistance through the deregulation of immune surveillance. A characteristic feature of the ovarian cancer TME is the ascites/peritoneal fluid, a malignancy-associated effusion occurring at more advanced stages, which enables the peritoneal dissemination of tumor cells and the formation of metastasis. The standard therapy for EOC involves a combination of debulking surgery and platinum-based chemotherapy. However, most patients experience disease recurrence. New therapeutic strategies are needed to improve the prognosis of patients with advanced EOC. Harnessing the body’s natural immune defenses against cancer in the form of immunotherapy is emerging as an innovative treatment strategy. NK cells have attracted attention as a promising cancer immunotherapeutic target due to their ability to kill malignant cells and avoid healthy cells. Here, we will discuss the recent advances in the clinical application of NK cell immunotherapy in EOC. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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Graphical abstract

14 pages, 3529 KiB

Open AccessReview

Interstitial Fluid in Gynecologic Tumors and Its Possible Application in the Clinical Practice

by Blendi Ura, Giovanni Di Lorenzo, Federico Romano, Lorenzo Monasta, Giuseppe Mirenda, Federica Scrimin and Giuseppe Ricci

Int. J. Mol. Sci. 2018, 19(12), 4018; https://doi.org/10.3390/ijms19124018 - 12 Dec 2018

Cited by 9 | Viewed by 4859

Abstract

Gynecologic cancers are an important cause of worldwide mortality. The interstitium consists of solid and fluid phases, situated between the blood vessels and cells. The interstitial fluid (IF), or fluid phase, is an extracellular fluid bathing and surrounding the tissue cells. The TIF [...] Read more.

Gynecologic cancers are an important cause of worldwide mortality. The interstitium consists of solid and fluid phases, situated between the blood vessels and cells. The interstitial fluid (IF), or fluid phase, is an extracellular fluid bathing and surrounding the tissue cells. The TIF (tumor interstitial fluid) is a dynamic fluid rich in lipids, proteins and enzyme-derived substances. The molecules found in the IF may be associated with pathological changes in tissues leading to cancer growth and metastatization. Proteomic techniques have allowed an extensive study of the composition of the TIF as a source of biomarkers for gynecologic cancers. In our review, we analyze the composition of the TIF, its formation process, the sampling methods, the consequences of its accumulation and the proteomic analyses performed, that make TIF valuable for monitoring different types of cancers. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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Other

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16 pages, 1974 KiB

Open AccessPerspective

S100A10 and Cancer Hallmarks: Structure, Functions, and its Emerging Role in Ovarian Cancer

by Tannith M. Noye, Noor A. Lokman, Martin K. Oehler and Carmela Ricciardelli

Int. J. Mol. Sci. 2018, 19(12), 4122; https://doi.org/10.3390/ijms19124122 - 19 Dec 2018

Cited by 31 | Viewed by 6444

Abstract

S100A10, which is also known as p11, is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of two subunits of annexin A2 and S100A10, activates the plasminogen activation pathway, which is involved in cellular repair of [...] Read more.

S100A10, which is also known as p11, is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of two subunits of annexin A2 and S100A10, activates the plasminogen activation pathway, which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin—which promotes the degradation of the extracellular matrix—increased angiogenesis, and the invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells, including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4-fold increased risk of progression and 7.9-fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer; however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding of S100A10 function in cancer with a particular focus on ovarian cancer. Full article

(This article belongs to the Special Issue Gynecologic Oncology: From Molecular Mechanisms to Targeted Therapies 2018)

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