Targeting gene-fibroblast interaction offers hope for treatment-resistant colon cancer

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A new research paper is published old age (listed by MEDLINE/PubMed as “Aging (Albany NY)” and Web of Science as “Aging-US”) Volume 16, Issue 2, Title, “PROX1 Interaction with α-SMA-Enriched Cancer-Associated Fibroblasts Facilitates Colorectal Cancer Progression and correlates with poor clinical outcomes and therapeutic resistance.”

The tumor microenvironment (TME) plays an important role in tumor progression through complex molecular interactions. Cancer-associated fibroblasts (CAFs), especially those expressing alpha-smooth muscle actin (α-SMA) or myofibroblasts, are helpful in this context and are associated with adverse outcomes in colorectal cancer (CRC). Although various transcription factors affect the TME, the exact regulator that causes CAF dysregulation in CRC remains elusive. Prospero Homeobox 1 (PROX1) is different, as its inhibition reduces α-SMA-rich CAF activity. However, the therapeutic role of PROX1 remains controversial due to inconsistent research results.

In this new study, researchers Dr Shiu-Wei Lai, Yi-Chiao Cheng, Ki-Thai Qiu, Min-Huan Yen, Ying-Wei Chen, Bijesh Kumar Yadav, Chi-Tai Yeh, Kuang-Tai Kuo, And Tung-Cheng Chang The National Defense Medical Center in Taipei, Taipei Medical University, Taipei Medical University Shuang-ho Hospital and National Taitung University used the ULCAN portal and noted an elevated PROX1 level in advanced colon adenocarcinoma, which is associated with a poor prognosis. Their experiments determined the effect of PROX1 overexpression on CRC cell characteristics, while co-culture experiments highlighted the PROX1-CAF relationship. Molecular expressions were verified by qRT-PCR and western blot alive Research is more robust observation.

“Our study emphasizes the link between PROX1 and α-SMA in CAFs.”

Elevated PROX1 in CRC samples correlates with increased α-SMA in tumors. PROX1 modulation affects the behavior of specific CRC cells, its overexpression promotes invasiveness. Kaplan-Meier evaluation demonstrated a link between PROX1 or α-SMA and survival outcomes. Consequently, PROX1, alone or together with α-SMA, emerged as a CRC prognostic marker. Co-culture and animal experiments have further highlighted this relationship.

PROX1 indicates the combined PROX1/α-SMA gene as a potential CRC prognostic marker, affecting CAFs within the TME appears to be important in altering CRC behavior and therapeutic resistance. The idea of ​​developing inhibitors targeting this gene set emerged as a potential therapeutic strategy. However, this study is bound by limitations, including the potential challenges of clinical translation, a focused investigation on PROX1/α-SMA potentially overlooking other significant molecular contributors, and the preliminary nature of the inhibitor development proposal.

“As we progress in this field, the development and clinical validation of small-molecule inhibitors targeting PROX1/α-SMA become imperative, paving the way to refine and optimize CRC therapeutic interventions.”

Source:

Journal Reference:

Lai, S.-W., etc. (2024). PROX1 interaction with α-SMA-rich cancer-associated fibroblasts facilitates colorectal cancer progression and correlates with poor clinical outcome and therapeutic resistance. old age. doi.org/10.18632/aging.205447.



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