Kidney, prostate, and bladder cancers increase with age and 82 percent of new cases occurred in individuals aged 60 years and older [26]. The research on the aging microenvironment in tumors is emerging, but the mechanism of its influence on patients of different ages with urogenital cancers is unclear. The development of gene sequencing and bioinformatics provides a feasible approach for us to explore the changes of the aging microenvironment in urogenital cancers from the perspective of bioinformatics analysis. Our study identified 14 central genes, 4 key cells and several potential pathways through bioinformatics analysis of potential and age-related genes and pathway changes in the urogenital cancers’ tumor microenvironment. Change of these genes and cells may influence age-induced genomic and clinical differences in urogenital cancers.
Age is one of the major factors affecting the prognosis of patients with urogenital cancers. In this study, elderly patients with bladder cancer and renal cell cancer had poorer overall survival and clinical staging compared with younger patients, which was consistent with other studies [27, 28]. However, there was no significant difference in prognosis between the old group and the young group in prostate cancer. This may be because only 10 deaths were observed in the TCGA database of 500 prostate cancer patients. However, a study of 259 cases of prostate cancer showed increased risk of poor cancer-specific survival in older patients with small-cell Carcinoma of the Prostate [29]. In conclusion, the prognosis in elderly patients with urogenital cancers is poor.
In this study, 14 hub genes were identified and may be the main factor causing differences in overall survival and clinical characteristics of patients of different age. All 14 hub genes and their functions are shown in Table 1. ORM1, ORM2 are conserved endoplasmic reticulum membrane proteins regulating lipid homeostasis and protein quality control [30]. HP has a strong correlation with ORM1 ORM2, and these three genes play a role in many inflammatory diseases, such as sarcoidosis and chronic obstructive pulmonary disease [31, 32]. MYH6, MYH7 and MYH7B are important myosin heavy chain protein, and MYLPF is myosin light chain protein, and MYBPH is myosin binding protein. Mutations in these genes have been linked to various muscle-related diseases and heart disease [33]. CSRP3 is an autophagy regulating molecule that is essential for regulating the degradation of muscle-related components and maintaining normal muscle structure and function [34]. TCAP is a giant elastic protein with kinase activity that extends half the length of a sarcomere and maintains cellular structure [35]. TNNT3 is a fast skeletal muscle Troponin T (TnT), which is involved in initiating muscle contractions [36]. TRIM63 regulates proteasome degradation of cardiac troponin I/TNNI3 and other sarcomeric-associated proteins [37]. INSM1 and NEUROG3 are essential markers for pancreatic neuroendocrine tumors, and related diseases include gastrointestinal tumors, diarrhea and malabsorption [38, 39]. In summary, these hub genes are mainly involved in muscle structure and metabolism, as well as some inflammatory reactions and digestive diseases. Their relationship with aging and tumor needs further study and verification.
The enrichment analysis of age-related differentially expressed genes and co-expressed genes showed that these genes are mainly correlated with muscle structure and contraction regulation, ion channels related to muscle movement (Cl−, Ca2+), inflammatory response, antibacterial humoral immune response, substance metabolism and transport, redox reaction, etc. And pathways closely related to cancer include epithelial cell development, nuclear migration, etc. Cancer can be considered as an aging disease. Cancer and aging have many similar biological changes, including changes in intracellular communication, changes in protein stability, metabolic changes and mitochondrial dysfunction, etc. [40]. The biological changes related to age and cancer in this study were mainly changes in muscle activity and various inflammatory responses, which were not completely consistent with previous studies. With aging, myocardial and skeletal muscle movements decrease, and cumulative mutations lead to organ-specific genomic deterioration and dysfunction in old age [41]. Cancer and aging are characterized by similar metabolic disorders, including up-regulation of glycolysis and down-regulation of oxidative phosphorylation [42, 43]. Steroids changes, including adrenocorticosteroid, androgen, estrogen, etc., can promote the occurrence and development of some tumors, and prostate cancer is more relevant [44]. Inflammatory response mainly refers to the changes of immune cells and molecules, and immunosenescence is now closely related to cancer and aging [13, 14]. In all, the relationship between cancer and aging is not completely clear, and the relevant pathways in this study need to be further verified.
There are four cells related to age and tumor formation in the cellular microenvironment, which are Preadipocytes, CD4+ Tem, CD4+ T-cells, and CD8+ Tem. Age significantly affects normal cells in the tumor microenvironment (TME) and promotes tumor progression and metastasis. Fibroblasts and immune cells appear to be particularly vulnerable to this age-related effect [13]. The content of fibroblasts in tumor microenvironment decreased in elderly patients with prostate cancer. Preadipocytes, the only one stromal cell that shows differences in the three types of urogenital cancers, massively increased in elderly patients. The increase of adipose tissue in visceral tissue is one of the hallmarks of aging, which has been linked to cancer, and reduced adipocyte content can extend life [40, 45]. Preadipocytes are closely related to macrophages, and dysdifferentiate in old age, switching into a pro-inflammatory, tissue-remodeling, senescent-like state [45]. Another study shows that this action is achieved through the JAK pathway [46]. For immune cells, CD4+ Tem, CD4+ T-cells and CD8+ Tem were all decreased in elderly patients. It is almost common knowledge that poor immune function in the elderly, also named immunosenescence, can lead to impaired immune surveillance and increased the incidence of the cancer [14]. Immunosenescence causes almost all immune components to change, and CD4 cells and especially CD8 cells are particularly susceptible to immunosenescence [47]. Reversing the expression of these four cells in TME in elderly patients may promote the cure of cancer or alter its clinical characteristics.
In summary, our study identified several age-related genes, cells and pathways in patients with urogenital cancers. These findings can be well combined with age and urogenital cancers, and can be a good guide for further research. Although we have made comprehensive study correlated with tumor microenvironment changes and urogenital cancers, the experiments and clinical validation works with large samples are still necessary.