Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Kim, Iljin; Choi, Sanga; Yoo, Seongkyeong; Lee, Mingyu; Kim, In‐San

doi:10.3390/cancers14143321

Cited by 40 publications

(21 citation statements)

References 147 publications

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“…Additionally, since mitochondria plays an important role in metastasis by modulating metabolic and genetic responses to dynamic TME cues (46), it supports our observation that HKDC1 responds to hypoxia and needs assistance from CAFs to promote HCC metastasis. CAFs, one of the most critical TME components of liver cancer, are widely known for their roles in creating hypoxic TME and promoting tumor cell dissemination (47, 48). As HKDC1 is known to have a low HK activity and low expression in the normal liver (9, 10), it is conceivable that HKDC1 is not a primary nor classical HK in tumor cells but rather a stress responder, such as under acute hypoxia.…”

Section: Discussionmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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Background and AimsHexokinases (HKs), a group of enzymes catalyzing the first step of glycolysis, have been shown to play important roles in liver metabolism and tumorigenesis. Our recent studies identified HKDC1 as a top candidate associated with liver cancer metastasis. We aimed to compare its cell-type specificity with other HKs upregulated in liver cancer and investigate the molecular mechanisms underlying its involvement in liver cancer metastasis.Approach and ResultsWe found that, compared to HK1 and HK2, the other two commonly upregulated HKs in liver cancer, HKDC1 was most strongly associated with the metastasis potential of tumors and organoids derived from two liver cancer mouse models we previously established. RNA in situ hybridization and single-cell RNA-seq analysis revealed that HKDC1 was specifically upregulated in malignant cells in hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA) patient tumors, whereas HK1 and HK2 were widespread across various tumor microenvironment lineages. An unbiased metabolomic profiling demonstrated that HKDC1 overexpression in HCC cells led to metabolic alterations distinct from those from HK1 and HK2 overexpression, with HKDC1 particularly impacting the tricarboxylic acid (TCA) cycle. HKDC1 was prometastatic in HCC orthotopic and tail vein injection mouse models and, molecularly, HKDC1 was induced by hypoxia and bound to glycogen synthase kinase 3β to stabilize β-catenin, leading to enhanced stemness of HCC cells.ConclusionsOverall, our findings underscore HKDC1 as a prometastatic HK specifically expressed in the malignant compartment of primary liver tumors, thereby providing a mechanistic basis for targeting this enzyme in advanced liver cancer.

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Section: Discussionmentioning

confidence: 99%

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Fan,

Tian,

Yang

et al. 2024

Preprint

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“…Rapidly dividing tumor cells create a hypoxic environment [ 43 ] and force the tumor to adapt to hypoxia by changing its gene expression pattern to resist hypoxia-induced cell death [ 44 ]. The macrophages exposed to hypoxia accumulate HIF1α and HIF2α [ 45 ], thereby promoting tumor growth through the controlled PI3K signaling pathway [ 46 ].…”

Section: Discussionmentioning

confidence: 99%

Tumor micronecrosis predicts poor prognosis of patients with hepatocellular carcinoma after liver transplantation

Wang

Zhang

et al. 2023

BMC Cancer

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Background Tumor micronecrosis is a histopathological feature predicting poor prognosis in patients with hepatocellular carcinoma (HCC) who underwent liver resection. However, the role of tumor micronecrosis in liver transplantation remains unclear. Methods We retrospectively reviewed patients with HCC who underwent liver transplantation between January 2015 and December 2021 at our center. We then classified them into micronecrosis(−) and micronecrosis(+) groups and compared their recurrence-free survival (RFS) and overall survival (OS). We identified independent prognostic factors using Cox regression analysis and calculated the area under the receiver operating characteristic curve (AUC) to evaluate the predictive value of RFS for patients with HCC after liver transplantation. Results A total of 370 cases with evaluable histological sections were included. Patients of the micronecrosis(+) group had a significantly shorter RFS than those of the micronecrosis(−) group (P = 0.037). Shorter RFS and OS were observed in micronecrosis(+) patients without bridging treatments before liver transplantation (P = 0.002 and P = 0.007), while no differences were detected in those with preoperative antitumor therapies that could cause iatrogenic tumor necrosis. Tumor micronecrosis improved the AUC of Milan criteria (0.77–0.79), the model for end-stage liver disease score (0.70–0.76), and serum alpha-fetoprotein (0.63–0.71) for the prediction of prognosis after liver transplantation. Conclusion Patients with HCC with tumor micronecrosis suffer from a worse prognosis than those without this feature. Tumor micronecrosis can help predict RFS after liver transplantation. Therefore, patients with HCC with tumor micronecrosis should be treated with adjuvant therapy and closely followed after liver transplantation. Clinical trials registration Not Applicable.

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“…At the same time, a local oxygen gradient appears in CAF in the TME that aids tumor subclonal evolution, resulting in further intratumor heterogeneity 36 . Through aberrant paracrine signaling and matrix remodeling, the niches necessary to maintain cancer stem cells are generated 37,38,39,40 and the angiogenic signals stimulated by hypoxia support endothelial sprouting and tumor growth as well 24,41,42,43,44,45 .…”

Section: Discussionmentioning

confidence: 99%

Concordance and deviations of the PDX tumors from the primary tumors of NSCLC patients: effects of murine fibroblasts on low engraftment rates

Lee

Seo

Kim

et al. 2023

Preprint

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Patient-derived xenograft(PDX) models of primary lung cancer have been reported. However, varying engraftment rates and their underlying mechanisms for specific subtypes of lung cancer (adenocarcinoma, squamous cell carcinoma, and large cell neuroendocrine carcinoma) have not been studied. The authors prepared subcutaneous tumors grown in NSG™ mice with primary tumors of lung cancer patients to develop lung cancer PDX models. Pathological features of the subcutaneous tumors were compared with those of the patients. One hundred seventeen lung cancer PDX models retaining the original pathologic features were obtained from 642 primary lung cancer patients. Nineteen PDX tumors and the corresponding patient tumors, representing three subtypes of cell lung cancer, were selected and analyzed with in-depth genomic and transcriptomic profiling. Results showed the PDX tumors retained most of the somatic and oncogenic mutations with limited levels of additional xenograft-specific mutations. Significant downregulation of the genes involved in hypoxia-associated angiogenesis was found compared with the corresponding human tumors. This downregulation was associated with murine fibroblasts in the PDX tumor microenvironment, which might be an important factor in low engraftment rates in primary lung cancer PDX models.

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Cancer-Associated Fibroblasts in the Hypoxic Tumor Microenvironment

Cited by 40 publications

References 147 publications

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

HKDC1 Promotes Liver Cancer Stemness Under Hypoxia via Stabilizing β-Catenin

Tumor micronecrosis predicts poor prognosis of patients with hepatocellular carcinoma after liver transplantation

Concordance and deviations of the PDX tumors from the primary tumors of NSCLC patients: effects of murine fibroblasts on low engraftment rates

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