Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

Chang, Wei‐Min; Lin, Yu-Fung; Su, Chih-Chung; Peng, Hsuan Yu; Chang, Yu Chan; Hsiao, Jenn Ren; Chen, Chi Long; Chang, Jang Yang; Shieh, Yi‐Shing; Hsiao, Michael; Shiah, Shine-Gwo

doi:10.1038/srep41131

Cited by 43 publications

(47 citation statements)

References 48 publications

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“…Besides its physiologic role as master regulator of osteogenic differentiation, several studies confirmed the tumor‐promoting role of RUNX2 in different cancer entities, including HNSCC (22, 36–39). Ectopic RUNX2 expression leads to an increased parathyroid hormone–like hormone expression and promotes proliferation of HNSCC cells (40). Moreover, RUNX2 was up‐regulated in HNSCC with lymph node metastasis and predicted poor prognosis in patients with HNSCC.…”

Section: Discussionmentioning

confidence: 99%

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Wessely¹,

Waltera²,

Reichert³

et al. 2019

The FASEB Journal

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Mesenchymal stem cells (MSCs) are multipotent progenitor cells capable of differentiating into adipocytic, osteogenic, chondrogenic, and myogenic lineages. There is growing evidence that MSCs home into the tumor microenvironment attracted by a variety of signals such as chemokines, growth factors, and cytokines. Tumor‐homing stem cells may originate from bone marrow–derived MSCs (BMSCs) or adipose tissue‐derived MSCs. Recent scientific data suggest that MSCs in combination with tumor cells can either promote or inhibit tumorigenic behavior. In head and neck squamous cell carcinoma (HNSCC), BMSCs are reported to be enriched with a potential negative role. Here, we evaluated the effect of BMSCs from 4 different donors in combination with 4 HNSCC cell lines in a 3‐dimensional multicellular spheroid model. Heterogeneous combinations revealed an up‐regulation of gene and protein expression of osteogenic markers runt‐related transcription factor 2 (RUNX2) and alkaline phosphatase (ALP) together with a substantial secretion of matrix metalloproteinase 9. Moreover, heterogenous BMSC/tumor spheroids showed increased invasion compared with homogenous spheroids in a Boyden chamber invasion assay. Furthermore, inhibition of ALP resulted in a substantially decreased spreading of heterogeneous spheroids on laminin‐rich matrix. In summary, our data suggest a prometastatic effect of BMSCs combined with HNSCC.—Wessely, A., Waltera, A., Reichert, T. E., Stöckl, S., Grässel, S., Bauer, R. J. Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D‐spheroids. FASEB J. 33, 11884–11893 (2019). http://www.fasebj.org

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Section: Discussionmentioning

confidence: 99%

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Wessely¹,

Waltera²,

Reichert³

et al. 2019

The FASEB Journal

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“…Cancer cells are one source of PTHrP, which causes humoral hypercalcemia and promotes the osteolytic bone metastases of a malignancy by activating the type 1 PTH/PTHrP receptor (PTH1R) in the kidneys and skeleton [36]. PTHrP is also implicated in the regulation of the behavior of primary cancer by the paracrine/autocrine action model, including cell proliferation, migration, and invasion, and prevents cell death in different types of cancers [37,38,39]. PTHrP supports the metastatic potential of prostate cancer by protecting tumor cells from anoikis in both in vitro and in vivo models [40].…”

Section: Discussionmentioning

confidence: 99%

Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1

Hsu

Chen

Chang

et al. 2018

IJMS

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Crosstalk of a tumor with its microenvironment is a critical factor contributing to cancer development. This study investigates the soluble factors released by tumor-associated dendritic cells (TADCs) responsible for increasing cancer stem cell (CSC) properties, cell mobility, and epithelial-to-mesenchymal transition (EMT). Dendritic cells (DCs) of colon cancer patients were collected for phenotype and CXCL1 expression by flow cytometry and Luminex assays. The transcriptome of CXCL1-treated cancer cells was established by next generation sequencing. Inflammatory chemokine CXCL1, present in large amounts in DCs isolated from colon cancer patients, and SW620-conditioned TADCs, enhance CSC characteristics in cancer, supported by enhanced anchorage-independent growth, CD133 expression and aldehyde dehydrogenase activity. Additionally, CXCL1 increases the metastatic ability of a cancer by enhancing cell migration, matrix metalloproteinase-7 expression and EMT. The enhanced CXCL1 expression in DCs is also noted in mice transplanted with colon cancer cells. Transcriptome analysis of CXCL1-treated SW620 cells indicates that CXCL1 increases potential oncogene expression in colon cancer, including PTHLH, TYRP1, FOXO1, TCF4 and ZNF880. Concurrently, CXCL1 displays a specific microRNA (miR) upregulated by the prototypical colon cancer onco-miR miR-105. Analysis of publicly available data reveals CXCL1-driven oncogenes and miR-105 have a negative prognostic impact on the outcome of colon cancer. This study indicates a new mechanism by which the colon cancer milieu exploits DC plasticity to support cancer progression.

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“…PTHLH aids in regulating cell differentiation and proliferation, particularly in bone development, and promotes cell migration and invasion [16,17]. A significant prevention of apoptosis has also been observed with PTHLH upregulation [15]. RUNX2 (runt-related transcription factor 2), another gene involved in osteoblast differentiation, may stimulate PTHLH expression through IHH (Indian Hedgehog) [15], both of whose expressions are upregulated in our metastatic model when compared to the muscle model (Figure 4a).…”

Section: Discussionmentioning

confidence: 62%

“…The 47 genes identified in the mouse comparison were analyzed across the human tumors, and only one gene was found to be significantly different: parathyroid hormone-like hormone (PTHLH) (p-value = 0.0391, 95% CI = −2.56 to −0.068) (Figure 4c) (Supplemental Table S3). This gene is intriguing in that it is downstream of RUNX2, a master regulator of bone development and ossification, and a high expression has been correlated to a faster disease progression in a number of cancers (i.e., colon, prostate, breast, head, and neck) due to the overexpression of PTHLH [15][16][17][18]. Among its putative functions for cancer progression is the activation of myeloid-derived suppressor cells (MDSCs) in the bone marrow [18].…”

Section: Underlying Gene Expression Of Bone Development Genes In Metamentioning

confidence: 99%

Underlying Ossification Phenotype in a Murine Model of Metastatic Synovial Sarcoma

Kirkham

Kalivas

Fatema

et al. 2020

IJMS

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Synovial sarcoma, an uncommon cancer, typically affects young adults. Survival rates range from 36% to 76%, decreasing significantly when metastases are present. Synovial sarcomas form in soft tissues, often near bones, with about 10% demonstrating ossification in the tumor. The literature is inconclusive on whether the presence of ossification portends a worse prognosis. To this end, we analyzed our genetic mouse models of synovial sarcoma to determine the extent of ossification in the tumors and its relationship with morbidity. We noted higher ossification within our metastatic mouse model of synovial sarcoma. Not only did we observe ossification within the tumors at a frequency of 7%, but an even higher frequency, 72%, of bone reactivity was detected by radiography. An enrichment of bone development genes was associated with primary tumors, even in the absence of an ossification phenotype. In spite of the ossification being intricately linked with the metastatic model, the presence of ossification was not associated with a faster or worse morbidity in the mice. Our conclusion is that both metastasis and ossification are dependent on time, but that they are independent of one another.

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Parathyroid Hormone-Like Hormone is a Poor Prognosis Marker of Head and Neck Cancer and Promotes Cell Growth via RUNX2 Regulation

Cited by 43 publications

References 48 publications

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Induction of ALP and MMP9 activity facilitates invasive behavior in heterogeneous human BMSC and HNSCC 3D spheroids

Interaction between Tumor-Associated Dendritic Cells and Colon Cancer Cells Contributes to Tumor Progression via CXCL1

Underlying Ossification Phenotype in a Murine Model of Metastatic Synovial Sarcoma

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