Dataset Information

Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.

ABSTRACT: Inactivation of the tumor suppressor p53 through somatic mutations, observed in 50% of human cancers, is one of the leading causes of tumorigenesis. Clinical and experimental evidence also reveals that p53 mutations sometimes occur in tumor-associated fibroblasts, which correlate with an increased rate of metastases and poor prognosis, suggesting that p53 dysfunction in the tumor microenvironment (TME) favors tumor establishment and progression. To understand the impact of p53 inactivation in the TME in tumor progression, we compared the growth of subcutaneously inoculated B16F1 melanoma in p53(null) and wild-type (WT) mice. Interestingly, tumor growth in p53(null) mice was greatly accelerated, correlating with marked increases in CD11b(+)Gr-1(+) myeloid-derived suppressor cells (MDSC), FoxP3(+) regulatory T cells, and a loss of effector function, compared with those in WT mice. This augmented immunotolerant TME in p53(null) mice was associated with a marked expansion of a specialized stromal network in the tumor and spleen. These stromal cells expressed markers of fibroblastic reticular cells of lymphoid organs and were readily expanded in culture from p53(null), but not WT, mice. They produced high levels of inflammatory cytokines/chemokines and immunosuppressive molecules, thereby enhancing MDSC differentiation. Furthermore, they significantly accelerated tumor progression in WT mice when co-injected with B16F1. Together, our results show that tumor-stroma interaction in hosts with dysfunctional p53 exacerbates immunosuppression by expanding the lymphoid-like stromal network that enhances MDSC differentiation and tumor progression.

SUBMITTER: Guo G

PROVIDER: S-EPMC3602383 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.

Guo Gang G Marrero Luis L Rodriguez Paulo P Del Valle Luis L Ochoa Augusto A Cui Yan Y

Cancer research 20130114 6

Inactivation of the tumor suppressor p53 through somatic mutations, observed in 50% of human cancers, is one of the leading causes of tumorigenesis. Clinical and experimental evidence also reveals that p53 mutations sometimes occur in tumor-associated fibroblasts, which correlate with an increased rate of metastases and poor prognosis, suggesting that p53 dysfunction in the tumor microenvironment (TME) favors tumor establishment and progression. To understand the impact of p53 inactivation in th ...[more]

PMID: 23319800

Similar Datasets

Project description:Background and objectiveHepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and the DNA polymerase delta (POLD) family is significantly related to cancer prognosis. This study aimed to explore the significance of the POLD family in HCC via the DNA damage repair (DDR) pathway.MethodsData mining was conducted using bioinformatics methods. RNA sequencing and clinicopathological data were collected from The Cancer Genome Atlas, GTEx database and the Gumz Renal cohort. Statistical analyses were also performed in cancer samples (n>12,000) and the Affiliated Hospital of Youjiang Medical University for Nationalities (AHYMUN, n=107) cohort.ResultsThe POLD family (POLD1-4) was identified as the most important functional component of the DDR pathway. Based on the analysis of independent cohorts, we found significantly elevated POLD expression in HCC compared with normal tissues. Second, we investigated the prognostic implication of elevated POLD1 expression in HCC and pan-cancers, revealing that increased POLD1 levels were correlated to worse prognoses for HCC patients. Additionally, we identified 11 hub proteins interacting closely with POLD proteins in base excision repair, protein-DNA complex and mismatch repair signaling pathways. Moreover, POLD1 mutation functioned as an independent biomarker to predict the benefit of targeted treatment. Importantly, POLD1 expression was associated with immune checkpoint molecules, including CD274, CD80, CD86, CTLA4, PDCD1 and TCGIT, and facilitated an immune-excluded tumor microenvironment. Additionally, we confirmed that elevated POLD1 expression was closely correlated with the aggressive progression and poor prognosis of HCC in the real-world AHYMUN cohort.ConclusionWe identified a significant association between elevated POLD1 expression and poor patient survival and immune-excluded tumor microenvironment of HCC. Together, these findings indicate that POLD1 provides a valuable biomarker to guide the molecular diagnosis and development of novel targeted therapeutic strategies for HCC patients.

Project description:The stromal cells in the tumor microenvironment (TME) can influence the progression of multiple types of cancer; however, data on oral squamous cell carcinoma (OSCC) are limited. In the present study, the effects of verrucous squamous cell carcinoma‑associated stromal cells (VSCC‑SCs), squamous cell carcinoma‑associated stromal cells (SCC‑SCs) and human dermal fibroblasts (HDFs) on the tumor nest formation, proliferation, invasion and migration of HSC‑3 cells were examined in vitro using Giemsa staining, MTS, and Transwell (invasion and migration) assays, respectively. The results revealed that both the VSCC‑SCs and SCC‑SCs inhibited the tumor nest formation, and promoted the proliferation, invasion and migration of OSCC cells in vitro. Furthermore, the effects of VSCC‑SCs, SCC‑SCs and HDFs on the differentiation, proliferation, invasion and migration of OSCC cells in vivo were evaluated by hematoxylin and eosin staining, tartrate‑resistant acid phosphatase staining, immunohistochemistry and double‑fluorescent immunohistochemical staining, respectively. The results demonstrated that the VSCC‑SCs promoted the differentiation, proliferation, invasion and migration of OSCC cells, while the SCC‑SCs inhibited the differentiation, and promoted the proliferation, invasion and migration of OSCC cells in vivo. Finally, microarray data were used to predict genes in VSCC‑SCs and SCC‑SCs that may influence the progression of OSCC, and those with potential to influence the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. It was found that C‑X‑C motif chemokine ligand (CXCL)8, mitogen‑activated protein kinase 3 (MAPK3), phosphatidylinositol‑4,5‑bisphosphate 3‑kinase catalytic subunit alpha (PIK3CA), C-X-C motif chemokine ligand 1 (CXCL1) and C‑C motif chemokine ligand 2 (CCL2) may be involved in the crosstalk between VSCC‑SCs, SCC‑SCs and OSCC cells, which regulates the progression of OSCC. Intercellular adhesion molecule 1 (ICAM1), interleukin (IL)1B, Fos proto‑oncogene, AP‑1 transcription factor subunit (FOS), bone morphogenetic protein 4 (BMP4), insulin (INS) and nerve growth factor (NGF) may be responsible for the differential effects of VSCC‑SCs and SCC‑SCs on the differentiation of OSCC. On the whole, the present study demonstrates that both VSCC‑SCs and SCC‑SCs may promote the progression of OSCC, and SCC‑SCs were found to exert a more prominent promoting effect; this may represent a potential regulatory mechanism for the progression of OSCC.

Dataset Information

Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.

Publications

Trp53 inactivation in the tumor microenvironment promotes tumor progression by expanding the immunosuppressive lymphoid-like stromal network.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets