Isabel Soto-Cruz

The Vaginal Microbiome and Host Health: Implications for Cervical Cancer Progression

The vaginal microbiome plays a crucial role in maintaining host health by preserving a balanced microenvironment. Nevertheless, the definition of a “normal” vaginal microbiome remains controversial, as its composition varies depending on factors such as ethnicity and geographical origin. In most cases, members of the genus Lactobacillus predominate in healthy vaginal microbiomes, protecting against potential pathogens through specific mechanisms such as the secretion of lactic acid and bacteriocins, among others. A reduction in Lactobacillus abundance, accompanied by an increase in anaerobic organisms, predisposes the host to the development of various pathologies. Among these pathologies is infection with human papillomavirus (HPV) and the subsequent development of cervical cancer. A progressive decline in Lactobacillus has been observed as the lesion advances in different populations worldwide. In the case of the Mexican population, several Lactobacillus have been reported in healthy microbiomes: L. gasseri, L. fermentum, L. rhamnosus, L. jensenii, L. crispatus, L. delbrueckii, L. acidophilus, and L. brevis. In contrast, genera reported in dysbiosis include Sneathia, while Brevibacterium aureum and Brachybacterium conglomeratum have been associated with HPV16 infection and/or SIL. The mere presence of some bacteria is not sufficient to modulate the cellular activity of host cells; therefore, the expression, production and activity of different proteins could be affected by the vaginal microbiome. The impact of the microbiome on host cell function is the result of different metabolites produced by the bacteria, which suppress or activate different signaling and metabolic pathways. The molecular interactions between the host and microbiome, as well as their role in cervical carcinogenesis, are still unknown. In this review, we focus on the vaginal microbiome, HPV, and the impact that the interaction of the microbiome with HPV has in cervical cancer development.

Cervical Cancer Cells Use the CD95 and IL-2 Pathways to Promote Their Proliferation and Survival

Cervical cancer is a global health problem; therapies focused on eliminating tumour cells and strengthening different immunotherapies are in development. However, it has been observed that cervical tumour cells can evade cell death mechanisms and generate immune system molecules to promote their proliferation and metastasis. In this context, we analysed the role of the IL-2 and CD95 pathways, essential molecules in activating the immune system and eliminating tumour cells. However, it is important to analyse their role in cervical tumour cells because these cells could be using these pathways to proliferate. In this study, we found that SiHa and HeLa cells respond to treatment, with 10 IU/mL of IL-2 inducing their proliferation and 100 IU/mL of IL-2 decreasing their proliferation. We also observed that they express a high percentage of the CD95 receptor and its ligand (CD95L) and that treatment with CD95 agonist antibodies at low doses increases cell proliferation. Furthermore, simultaneous treatment with high doses of IL-2 plus CD95 agonist antibody positively regulates LC3B accumulation. We did not observe apoptosis under any of the treatments carried out. In conclusion, cervical tumour cells can use the IL-2 and CD95 pathways to induce their proliferation and potentially activate cytoprotective mechanisms for survival.

STAT5 Is Necessary for the Metabolic Switch Induced by IL-2 in Cervical Cancer Cell Line SiHa

The tumor cells reprogram their metabolism to cover their high bioenergetic demands for maintaining uncontrolled growth. This response can be mediated by cytokines such as IL-2, which binds to its receptor and activates the JAK/STAT pathway. Some reports show a correlation between the JAK/STAT pathway and cellular metabolism, since the constitutive activation of STAT proteins promotes glycolysis through the transcriptional activation of genes related to energetic metabolism. However, the role of STAT proteins in the metabolic switch induced by cytokines in cervical cancer remains poorly understood. In this study, we analyzed the effect of IL-2 on the metabolic switch and the role of STAT5 in this response. Our results show that IL-2 induces cervical cancer cell proliferation and the tyrosine phosphorylation of STAT5. Also, it induces an increase in lactate secretion and the ratio of NAD+/NADH, which suggest a metabolic reprogramming of their metabolism. When STAT5 was silenced, the lactate secretion and the NAD+/NADH ratio decreased. Also, the expression of HIF1α and GLUT1 decreased. These results indicate that STAT5 regulates IL-2-induced cell proliferation and the metabolic shift to aerobic glycolysis by regulating genes related to energy metabolism. Our results suggest that STAT proteins modulate the metabolic switch in cervical cancer cells to attend to their high demand of energy required for cell growth and proliferation.

Role of the JAK/STAT Pathway in Cervical Cancer: Its Relationship with HPV E6/E7 Oncoproteins

The janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway is associated with the regulation of essential cellular mechanisms, such as proliferation, invasion, survival, inflammation, and immunity. Aberrant JAK/STAT signaling contributes to cancer progression and metastatic development. STAT proteins play an essential role in the development of cervical cancer, and the inhibition of the JAK/STAT pathway may be essential for enhancing tumor cell death. Persistent activation of different STATs is present in a variety of cancers, including cervical cancer, and their overactivation may be associated with a poor prognosis and poor overall survival. The oncoproteins E6 and E7 play a critical role in the progression of cervical cancer and may mediate the activation of the JAK/STAT pathway. Inhibition of STAT proteins appears to show promise for establishing new targets in cancer treatment. The present review summarizes the knowledge about the participation of the different components of the JAK/STAT pathway and the participation of the human papillomavirus (HPV) associated with the process of cellular malignancy.

NK Cell Regulation in Cervical Cancer and Strategies for Immunotherapy

Cervical cancer is one of the most prevalent gynaecological malignancies worldwide and is related to human papillomavirus (HPV) infection, viral persistence, progression, and invasion. Therefore, the immune response is linked to HPV status. Natural killer (NK) cells play a central role against virus-infected cells and tumours through a delicate balance between activating and inhibitory receptors and secretion of cytokines and chemokines. These cells also play a crucial role in tumour immunosurveillance. For these reasons, there is growing interest in harnessing NK cells as an immunotherapy for cervical cancer. These studies are diverse and include many strategies such as transferring activated autologous or allogeneic NK cells, improving the activation and cytolytic activity of NK cells using cytokines or analogues and modifying chimeric antigen receptors to increase specificity and targeting NK cells. However, research regarding the application of NK cells in immunotherapy is limited. This article focuses on recent discoveries about using NK cells to prevent and treat cervical cancer and the possibility of cellular immunotherapy becoming one of the best strategies to exploit the immune system to fight tumours.

JAK/STAT Signaling and Cervical Cancer: From the Cell Surface to the Nucleus

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway constitutes a rapid signaling module from the cell surface to the nucleus, and activates different cellular responses, such as proliferation, survival, migration, invasion, and inflammation. When the JAK/STAT pathway is altered, it contributes to cancer progression and metastasis. STAT proteins play a central role in developing cervical cancer, and inhibiting the JAK/STAT signaling may be necessary to induce tumor cell death. Several cancers show continuous activation of different STATs, including cervical cancer. The constitutive activation of STAT proteins is associated with a poor prognosis and overall survival. The human papillomavirus (HPV) oncoproteins E6 and E7 play an essential role in cervical cancer progression, and they activate the JAK/STAT pathway and other signals that induce proliferation, survival, and migration of cancer cells. Moreover, there is a crosstalk between the JAK/STAT signaling cascade with other signaling pathways, where a plethora of different proteins activate to induce gene transcription and cell responses that contribute to tumor growth. Therefore, inhibition of the JAK/STAT pathway shows promise as a new target in cancer treatment. In this review, we discuss the role of the JAK/STAT pathway components and the role of the HPV oncoproteins associated with cellular malignancy through the JAK/STAT proteins and other signaling pathways to induce tumor growth.