HIPK2 role in the tumor–host interaction: Impact on fibroblasts transdifferentiation CAF‐like
| Autor: | Mara Cirone, Alessia Garufi, Gabriella D'Orazi, Gianandrea Traversi |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Clinical Biochemistry HIPK2 Protein Serine-Threonine Kinases Biology Biochemistry Metastasis cancer‐associated fibroblast (CAF) 03 medical and health sciences 0302 clinical medicine Immune system Cancer-Associated Fibroblasts Downregulation and upregulation Tumor Microenvironment Genetics medicine Humans fibroblast transdifferentiation Molecular Biology Cells Cultured Tumor microenvironment Transdifferentiation Cancer Cell Biology Hypothesis Fibroblasts medicine.disease cancer progression 030104 developmental biology Tumor progression Culture Media Conditioned 030220 oncology & carcinogenesis Cell Transdifferentiation Colonic Neoplasms Cancer cell Cancer research caveolin‐1 Carrier Proteins reactive‐oxygen species (ROS) |
| Zdroj: | Iubmb Life |
| ISSN: | 1521-6551 1521-6543 |
| DOI: | 10.1002/iub.2144 |
| Popis: | The dialogue between cancer cells and the surrounding fibroblasts, tumor‐associated macrophages (TAM), and immune cells can create a tumor microenvironment (TME) able to promote tumor progression and metastasis and induce resistance to anticancer therapies. Cancer cells, by producing growth factors and cytokines, can recruit and activate fibroblasts in the TME inducing their transdifferention in cancer‐associated fibroblasts (CAFs). Then, CAFs, in a reciprocal cross‐talk with cancer cells, sustain cancer growth and survival and support malignancy and tumor resistance to therapies. Therefore, the identification of the molecular mechanisms regulating the interplay between cancer cells and fibroblasts can offer an intriguing opportunity for novel diagnostic and therapeutic anticancer purpose. HIPK2 is a multifunctional tumor suppressor protein that modulates cancer cell growth and apoptosis in response to anticancer drugs and negatively regulates pathways involved in tumor progression and chemoresistance. HIPK2 protein downregulation is induced by hypoxia and hyperglycemia and HIPK2 knockdown favors tumor progression and resistance to therapy other than a pseudohypoxic, inflammatory, and angiogenic cancer phenotype. Therefore, we hypothesized that HIPK2 modulation in cancer cells could contribute to modify the tumor–host interaction. In support of our hypothesis, here we provide evidence that culturing human fibroblasts (hFB) with conditioned media derived from cancer cells undergoing HIPK2 knockdown (CMsiHIPK2) triggered their transdifferentiation CAF‐like, compared to hFB cultured with CM‐derived from HIPK2‐carrying control cancer cells. CAF transdifferentiation was identified by expression of several markers including α‐smooth muscle actin (α‐SMA) and collagen I and correlated with autophagy–mediated caveolin‐1 degradation. Although the molecular mechanisms dictating CAF‐transdifferentiation need to be elucidated, these results open the way to further study the role of HIPK2 in TME remodeling for prognostic and therapeutic purpose. |
| Databáze: | OpenAIRE |
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