Abstract
Previous studies have demonstrated that direct targeting of interstitial cancer-associated fibroblasts (CAF) and tumor fibrosis alone seemed to be an unpromising treatment option for malignant tumors. Therefore, it is necessary to further explore the mechanism of the influence of collagen and tumor fibrosis on the biological behavior of malignant tumors. The current study aimed to explore the effect of intratumor fibrosis on the prognosis of renal clear cell carcinoma (ccRCC) and its mechanism. With the bioinformatic analysis of The Cancer Genome Atlas (TCGA) database (n = 537), the study showed that high Collagen type I α 1 (COL1A1) mRNA expression indicated the poor prognosis of ccRCC patients compared with low expression ones. We further used the Two-photon-excited fluorescence (TPEF)/second harmonic generation (SHG) microscopy to determine the intratumor fibrosis of 68 patients with surgical resection of ccRCC and confirmed that a high fibrosis level in the tumor was associated with a poor prognosis compared with patients with low expression (Progression-Free Survival: p = 0.030). We further measured the protein chips of 640 cytokines in ccRCC specimens and found that several cytokines, including prolactin (PRL), were associated with the degree of fibrosis in the tumor, as confirmed by the prolactin receptor (PRLR) immunohistochemical method. In addition, the study showed that PRLR expression decreased significantly in the ccRCC compared with adjacent normal tissue (p < 0.05). Our research shows that low expression of PRLR predicted the poor survival of the patient. We used the Cell Counting Kit-8 experiment, the transwell and the plate clone formation assay to evaluate the role of PRL in the 7860 and the ACHN cell lines. We found that PRL promoted ccRCC cell proliferation and migration. JAK-STAT3 activation was found in the high prolactin expression group by mass spectrum analysis. This study delineated the fibrosis-based tumor microenvironment characteristics of ccRCC. PRL/PRLR may be involved in the fibrosis process and are essential prognostic risk factors for ccRCC.
Highlights
The incidence of kidney cancer is increasing by 2% annually worldwide
Col1A1 mRNA in tumors reflects the expression of type I collagen
With the bioinformatic analysis of the The Cancer Genome Atlas (TCGA)-KIRC database (n = 537), the survival curves in Figure 1 showed that high Col1A1 mRNA expression indicated poorer overall survival and disease- free
Summary
The incidence of kidney cancer is increasing by 2% annually worldwide. Renal clear cell carcinoma (ccRCC) is the primary pathological type of kidney cancer, accounting for almost 80% of the cases (Cairns, 2010). The primary treatment for patients with localized ccRCC is tumor resection, and metastasis is found in approximately 20% of patients at their first visit. Tumor Fibrosis treatment of ccRCC, approximately 30% of patients develop recurrence and metastasis. The 5-year survival rate of advanced ccRCC patients is only 23% (Rini et al, 2009). There is a need to identify the molecular mechanisms underlying the proliferative and invasive phenotype of ccRCC to identify early diagnostic and prognostic markers and potential therapeutic targets
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