Arturo Valle-Mendiola

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.

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.