Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis

Wei, Rui; Lv, Mengqin; Li, Fēi; Cheng, Teng; Zhang, Zhengzhong; Jiang, Guiying; Zhou, Ying; Gao, Ruiqiu; Wu, Xiao; Lou, Jiao; Wu, Xizi; Luo, Danfeng; Ma, Xiangyi; Jen, Jin; Ma, Ding; Liu, Xi

doi:10.18632/oncotarget.18621

Cited by 34 publications

(30 citation statements)

References 31 publications

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“…Ovarian cancer cell expression HOXA9 induces CAFs to secrete CXCL12, IL-6, and VEGF-A expression, which promotes angiogenesis [ 87 ]. Ovarian cancer CAFs have also been shown to induce angiogenesis by secreting VEGF-C as a result of induction by Sonic Hedgehog (SHH) from ovarian cancer cells [ 88 ]. While angiogenesis can be induced by cancer cells as well as the tumor microenvironment, CAFs are important direct or indirect contributors to the process, and hence towards cancer progression.…”

Section: Caf Functionsmentioning

confidence: 99%

Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression

Dasari

Fang

Mitra

2018

Cancers

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Ovarian cancer is the most lethal gynecologic malignancy, and patient prognosis has not improved significantly over the last several decades. In order to improve therapeutic approaches and patient outcomes, there is a critical need for focused research towards better understanding of the disease. Recent findings have revealed that the tumor microenvironment plays an essential role in promoting cancer progression and metastasis. The tumor microenvironment consists of cancer cells and several different types of normal cells recruited and reprogrammed by the cancer cells to produce factors beneficial to tumor growth and spread. These normal cells present within the tumor, along with the various extracellular matrix proteins and secreted factors, constitute the tumor stroma and can compose 10–60% of the tumor volume. Cancer associated fibroblasts (CAFs) are a major constituent of the tumor microenvironment, and play a critical role in promoting many aspects of tumor function. This review will describe the various hypotheses about the origin of CAFs, their major functions in the tumor microenvironment in ovarian cancer, and will discuss the potential of targeting CAFs as a possible therapeutic approach.

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Section: Caf Functionsmentioning

confidence: 99%

Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression

Dasari

Fang

Mitra

2018

Cancers

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“…Wei and coauthors recently demonstrated that SHH ligands increase PTCH1 and Gli1 expression leading to Hh signaling pathway activation in human CAF but not in normal fibroblasts. In the same study, Hh signaling stimulation augmented CAF proliferation and confirmed lymphangiogenesis in a xenograft model [95]. The Hh pathway also supports tumor cell invasion by stimulating cell motility and MMPs expression and by directly targeting genes implicated in EMT.…”

Section: Hh Signaling In Cancer-associated Fibroblastsmentioning

confidence: 65%

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

Bellei

Caputo

Carbone

et al. 2020

IJMS

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Nevoid basal cell carcinoma syndrome (NBCCS), also named Gorlin syndrome, is a rare multisystem genetic disorder characterized by marked predisposition to basal cell carcinomas (BCCs), childhood medulloblastomas, maxillary keratocysts, celebral calcifications, in addition to various skeletal and soft tissue developmental abnormalities. Mutations in the tumor suppressor gene PATCHED1 (PTCH1) have been found to be associated in the majority of NBCCS cases. PATCH1 somatic mutations and loss of heterozygosity are also very frequent in sporadic BCCs. Unlike non-syndromic patients, NBCCS patients develop multiple BCCs in sun-protected skin area starting from early adulthood. Recent studies suggest that dermo/epidermal interaction could be implicated in BCC predisposition. According to this idea, NBCCS fibroblasts, sharing with keratinocytes the same PTCH1 germline mutation and consequent constitutive activation of the Hh pathway, display features of carcinoma-associated fibroblasts (CAF). This phenotypic traits include the overexpression of growth factors, specific microRNAs profile, modification of extracellular matrix and basement membrane composition, increased cytokines and pro-angiogenic factors secretion, and a complex alteration of the Wnt/β-catenin pathway. Here, we review studies about the involvement of dermal fibroblasts in BCC predisposition of Gorlin syndrome patients. Further, we matched the emerged NBCCS fibroblast profile to those of CAF to compare the impact of cell autonomous “pre-activated state” due to PTCH1 mutations to those of skin tumor stroma.

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“…These changes are in accordance with the role of CAFs in tumor spread and their role in tumor stroma infi ltration and metastasis. As far as is known today, this role seems to be one of the most important for tumor agressiveness (41)(42)(43). Therefore, it seems plausible that the growth factors as well as others, still not complely understood soluble mediators produced and excreted by CAFs may have a role in both angio and lymphangiogenesis in breast carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Gustoća limfnih i malih krvnih žila u stromi tumora i peritumoralnog tkiva u invazivnom karcinomu dojke bez posebnih obilježja

Kos

Leniček

2018

lib oncl

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Background: Peritumoral clefts are noticed in carcinomas of many organs, and were thought to be artifacts due to fi xation and preparation of slides. Today they are considered to be additional marker of malignancy and the refl ection of epithelial-stromal interaction. The hypothesis was that peritumoral clefts in breast carcinoma refl ect changes in stromal composition and characteristics, and are related to lymphangiogenesis in tumor tissue. Materials and methods: One hunderd (59% with axillary lymph nodes metastases) invasive ductal breast carcinomas of no special type were analyzed for the presence and abundance of peritumoral clefts and immunohistochemically for CD34, vimentin, smooth muscle actin (SMA) and D2-40 (podoplanin) in tumor stroma. Results: Peritumoral clefts were found in 92% of invasive carcinomatous tissue and were absent in surrounding healthy tissue and around ducts of in situ component (with 5% do 100%. The threshold of 30% of peritumoral clefts was determined by receiver operating characteristic (ROC) analysis. The density of small lymphatic vessels in the stroma of the tumor, and outside the tumor tissue did not show signifi cant correlation with the threshold value. In patients with axillary metastases, peritumoral lymphovascular invasion (LVI) was found twice and intratumoral LVI fi ve times more often than in patients without axillary metastases. Neither peritumoral nor intratumoral LVI were signifi cantly correlated with the threshold value of 30%. In patients with axillary lymph node metasases, peritumoral lymphovascular invasion (LVI) was found twice as often, and intratumoral LVI 5 times as often than in patients without axillary lymph node metastases. Conclusion: Peritumoral clefts in invasive breast carcinoma refl ect stromal changes of fi broblasts and are not associated with lymphangiogenesis, that is probably caused by some other pathogenesis.

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Human CAFs promote lymphangiogenesis in ovarian cancer via the Hh-VEGF-C signaling axis

Cited by 34 publications

References 31 publications

Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression

Cancer Associated Fibroblasts: Naughty Neighbors That Drive Ovarian Cancer Progression

The Role of Dermal Fibroblasts in Nevoid Basal Cell Carcinoma Syndrome Patients: An Overview

Gustoća limfnih i malih krvnih žila u stromi tumora i peritumoralnog tkiva u invazivnom karcinomu dojke bez posebnih obilježja

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