腫瘍の微小環境は,HGFの分泌を通じてRAF阻害剤に対する先天的な耐性を誘発する
Ravid Straussman1, Teppei Morikawa, Kevin Shee
1The Eli and Edythe L. Broad Institute, 7 Cambridge Center, Cambridge, Massachusetts 02142, USA.
Nature
|July 6, 2012
まとめ
癌細胞だけでなく,腫瘍のマイクロ環境も薬剤耐性を引き起こします. ストロマ細胞は,がん薬の有効性を阻害する肝細胞成長因子 (HGF) などの因子を分泌し,がん細胞とストロマ細胞の両方を標的とした組み合わせ療法を示唆しています.
科学分野:
- 腫瘍学 腫瘍学
- がん生物学 がん生物学
- 腫瘍マイクロ環境の研究
背景:
- 癌患者の薬剤耐性は,重要な臨床的課題である.
- ほとんどの研究は,癌細胞の内在的な抵抗力メカニズムに焦点を当てています.
- 生まれながらの薬剤耐性を与える腫瘍の微環境の役割は,ますます認識されています.
研究 の 目的:
- 癌細胞の薬剤耐性に対する様々なストロマル細胞の影響を調査する.
- 腫瘍の微環境が抗がん剤に対する耐性を媒介する特定のメカニズムを特定する.
- ストロマ媒介薬剤耐性を克服するための新しい治療戦略を探求する.
主な方法:
- 23種類のストロマ細胞を45の癌細胞系と35の薬剤に対してテストするためのコカルチャーシステムの開発.
- 抵抗の分子媒介者を特定するためのプロテオミック分析.
- 患者のサンプルでの発見を検証するための免疫ヒストケミストリー.
- 治療の可能性を評価するための阻害研究.
主要な成果:
- ストロマル細胞は,一般的に抗がん剤,特に標的薬に対する生まれながらの耐性を授与する.
- 幹細胞によって分泌される肝細胞成長因子 (HGF) はMETを活性化し,MAPKとPI(3) K-AKT経路を活性化させ,BRAF変異性メラノーマではRAF阻害剤に対する即時の耐性を生み出します.
- ストロマルのHGF発現は,患者におけるRAF阻害剤に対する先天性耐性と相関する.
- 同様のレジスタンスメカニズムは,BRAF変異性大腸直腸腫および膠芽細胞腫細胞系において観察されました.
結論:
- 腫瘍の微環境は,先天的な薬剤耐性を媒介する上で重要な役割を果たします.
- HGFやその受容体METのようなストロマル因子をターゲットにすることで,RAF阻害剤と組み合わせて,BRAF変異性メラノーマの薬剤耐性を克服することができます.
- 腫瘍とストロマの相互作用を体系的に分析することは,薬剤耐性メカニズムの発見と効果的ながん治療法の開発に不可欠です.
さらに関連する動画
13:34A Combined 3D Tissue Engineered In Vitro/In Silico Lung Tumor Model for Predicting Drug Effectiveness in Specific Mutational Backgrounds
Published on: April 6, 2016
06:44Bioluminescence Resonance Energy Transfer (BRET)-Based Assay for Measuring Interactions of CRAF with 14-3-3 Proteins in Live Cells
Published on: March 1, 2024
関連する概念動画
03:03mTOR Signaling and Cancer Progression
The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The mTOR pathway or the...
02:38The Ras Gene
The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
Ras is a superfamily...
02:38Mitogens and the Cell Cycle
Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
02:17The Tumor Microenvironment
Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
02:17The Tumor Microenvironment
Every normal cell or tissue is embedded in a complex local environment called stroma, consisting of different cell types, a basal membrane, and blood vessels. As normal cells mutate and develop into cancer cells, their local environment also changes to allow cancer progression. The tumor microenvironment (TME) consists of a complex cellular matrix of stromal cells and the developing tumor. The cross-talk between cancer cells and surrounding stromal cells is critical to disrupt normal tissue...
01:24Small GTPases - Ras and Rho
Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
Three regulatory proteins control their activity: