Michor Franziska, Iwasa Yoh, Rajagopalan Harith, Lengauer Christoph, Nowak Martin A
Program for Evolutionary Dynamics, Harvard University, Cambridge, Massachusetts, USA.
Cell Cycle. 2004 Mar;3(3):358-62. Epub 2004 Mar 1.
Cancer results if regulatory mechanisms of cell birth and death are disrupted. Colorectal tumorigenesis is initiated by somatic or inherited mutations in the APC tumor suppressor gene pathway. Several additional genetic hits in other tumor suppressor genes and oncogenes drive the progression from polyps to malignant, invasive cancer. The majority of colorectal cancers present chromosomal instability, CIN, which is caused by mutations in genes that are required to maintain chromosomal stability. A major question in cancer genetics is whether CIN is an early event and thus a driving force of tumor progression. We present a new mathematical model of colon cancer initiation assuming a linear flow from stem cells to differentiated cells to apoptosis. We study the consequences of mutations in different cell types and calculate the conditions for CIN to precede APC inactivation. We find that early emergence of CIN is very likely in colorectal tumorigenesis.
如果细胞生死的调节机制被破坏，就会导致癌症。结直肠癌的发生是由APC肿瘤抑制基因途径中的体细胞或遗传性突变引发的。其他肿瘤抑制基因和癌基因中的一些额外基因损伤驱动了从息肉到恶性浸润性癌症的进展。大多数结直肠癌表现出染色体不稳定性（CIN），这是由维持染色体稳定性所需基因的突变引起的。癌症遗传学中的一个主要问题是CIN是否是一个早期事件，从而成为肿瘤进展的驱动力。我们提出了一个结肠癌起始的新数学模型，假设从干细胞到分化细胞再到凋亡存在线性流动。我们研究了不同细胞类型中突变的后果，并计算了CIN先于APC失活的条件。我们发现CIN在结直肠癌发生过程中很可能早期出现。
