Multidimensional outlook on the pathophysiology of cervical cancer invasion and metastasis

Abstract

Cervical cancer being one of the primary causes of high mortality rates among women is an area of concern, especially with ineffective treatment strategies. Extensive studies are carried out to understand various aspects of cervical cancer initiation, development and progression; however, invasive cervical squamous cell carcinoma has poor outcomes. Moreover, the advanced stages of cervical cancer may involve lymphatic circulation with a high risk of tumor recurrence at distant metastatic sites. Dysregulation of the cervical microbiome by human papillomavirus (HPV) together with immune response modulation and the occurrence of novel mutations that trigger genomic instability causes malignant transformation at the cervix. In this review, we focus on the major risk factors as well as the functionally altered signaling pathways promoting the transformation of cervical intraepithelial neoplasia into invasive squamous cell carcinoma. We further elucidate genetic and epigenetic variations to highlight the complexity of causal factors of cervical cancer as well as the metastatic potential due to the changes in immune response, epigenetic regulation, DNA repair capacity, and cell cycle progression. Our bioinformatics analysis on metastatic and non-metastatic cervical cancer datasets identified various significantly and differentially expressed genes as well as the downregulation of potential tumor suppressor microRNA miR-28-5p. Thus, a comprehensive understanding of the genomic landscape in invasive and metastatic cervical cancer will help in stratifying the patient groups and designing potential therapeutic strategies.

Keywords: Cervical squamous cell carcinoma; Genetic and epigenetic profile; Human papillomavirus; Lymph angiogenesis; Metastasis.

Fig. 1

The role of cervical epithelial cells in balancing the equilibrium of the local immune system. Cervical microenvironment and the local microbial diversity alter local and systemic immune response, which play an important role in the progression of CIN toward CC. Lactic-acid-producing bacteria acidify the vaginal milieu pH to 4.6 during eubiosis, with lactic acid as the primary metabolite, thereby providing a non-inflammatory environment. The dysbiotic environment would have a lower redox potential during microbial vaginosis, a phenomenon that encourages the growth of a diverse bacterial species, resulting in the increased pH. Virulence factors produced by the diverse bacterial species undermine epithelial barrier integrity, degrade mucin, and create a pro-inflammatory milieu

Fig. 2

Illustration showing the molecular signaling mechanisms by which CSCC undergoes epithelial–mesenchymal transition, lymph angiogenesis, and metastasis via the lymphatic system

Fig. 3

Differential gene expression and pathway analysis a An UpSetR plot of DEGs between metastatic and non-metastatic CC tissues retrieved from GEO database (DEGs; with log-fold change > =|1.5| and p-value <  = 0.05 cut-off) across five CC studies, b Protein–protein interaction network of the upregulated genes, c protein–protein interaction network of the downregulated genes, d top 10 hub genes upregulated in metastatic CC, e top 10 hub genes downregulated in metastatic CC. The hub genes are identified by the highest number of connections in the network. The color scale ranges from yellow (fewer interacting) to red (higher interacting) indicating the relative importance of the hub genes

Fig. 4

Functional enrichment analysis between metastatic and non-metastatic genes in CC a GO terms identification on the upregulated genes in molecular function, biological process and cellular component, b GO terms identification on the downregulated genes in molecular function, biological process and cellular component

Fig. 5

Pathway and network analysis a Top ten significant pathways enriched for pathway analysis through WikiPathways in upregulated genes, b host–Microbiome protein–domain interaction on upregulated genes, c mutation frequency of upregulated genes, d mutated genes which are upregulated in metastatic CC, e top ten significant pathways enriched for pathway analysis through WikiPathways in downregulated genes, f host–microbiome protein–domain interaction on downregulated genes, g Mutation frequency of downregulated genes, h mutated genes which are downregulated in metastatic CC i-n Needle plot for the mutations in IDS, MAP4K4, SPTBN1, COL4A2, KHDRBS1 and DST

Fig. 6

Immunohistochemistry image representation from Human Protein Atlas for IDS, MAP4K4, COL4A2, KHDRBS1, showing significant upregulation in CC and downregulation in normal cervix tissue. SPTBN1 and DST showed downregulation or not detected in CC with concurrent upregulation in normal tissue