A "conversion-deterioration-double mutation" theory for the evolution and progression of colorectal cancer

Abstract

In this study, based on some clinical phenomena and recently published knowledge, we proposed our "conversion-deterioration-double mutation" theory, which provides a possible unifying explanation for the evolutionary process of colorectal cancer cells in the human body. In this theory, we proposed that there is a partial interconversion and a jump conversion relationship among normal colorectal epithelial cells, colorectal cancer cells, stem cells, and cancer stem cells (conversion). This conversion leads to tumor heterogeneity. We also proposed that well-differentiated cancer cells converted from cancer stem cells have a more aggressive pattern than primary cancer cells (deterioration). The deterioration of primary cancer cells leads to differences in treatment responses and prognosis. Finally, we speculate a double mutation theory, indicating that for metastasis to occur, both mutations of cancer cells and mutations of target organs are needed and should match and meet. All these three points constitute the "conversion-deterioration-double mutation" theory.

Keywords: aberrant differentiation; cancer evolution; cancer stem cell; colorectal cancer; differentiation; metastasis; reprogramming; stem cell; tumor heterogeneity.

FIGURE 1

The partial interconversion and jump conversion relationships among normal epithelial cells, stem cells, non‐CSC CRC cells, and CSCs. In this figure, the solid line indicates a high possibility. The dotted line indicates a low possibility. (1) The orange arrow showed that the normal stem cells could convert into undifferentiated cancer cells/CSCs by de‐differentiation (rare). (2) The green arrows showed that how normal colorectal epithelial cells can convert into other types of cancer cells step‐by‐step by de‐differentiation (common). (3) The red arrows showed that normal colorectal epithelial cells sometimes can jump‐convert into other types of cells compared with green line by de‐differentiation (rare). (4) The blue arrow showed that cancer cells could directly convert into another type of cancer cells by reprogramming (rare). (5) The purple arrow showed that CSCs can divide and produce well differentiated but different cancer cells by re‐differentiation. (common), while these well differentiated but different cancer cells can convert into CSCs by de‐differentiation (common)

FIGURE 2

The metastasis and prognostic patterns of CRC. (1) In the red arrow approach, primary cancer cells migrate to the target organ, while there is a strong Mutation Y in the target organ, the primary cancer cells will adapt to the microenvironment well because of target organs' strong Mutation Y, and the metastatic cancer cells proliferate rapidly and form a metastatic lesion. As Mutation Y is a random event, which happens only small foci of target organ, the metastasis expresses an oligometastasis pattern. As they are primary cancer cells, they are chemosensitive and have a good prognosis after treatment. (2) Green arrow approach and blue arrow approach: primary cancer cells migrate to the target organ, while there is a weak Mutation Y in the target organ, the cancer cells do not adapt to the microenvironment well, the migrating cancer cells will not proliferate, and remain dormant. Because dormant cancer cells cannot maintain a large volume, the imaging examination cannot detect the metastatic lesion clinically, being considered as no evidence of metastasis. After removing the colorectal lesion, if prompt prophylactic chemotherapy is used, the dormant cancer cells will be killed, and the patients will be cured. If prompt prophylactic chemotherapy is not used, the dormant cancer cells will slowly undergo a de‐differentiation process, convert into CSCs, and succeed in re‐differentiated cancer cells, these CSCs and re‐differentiated cancer cells will adapt to the microenvironment of the target organ well and proliferate rapidly, expressing a metachronous metastasis pattern, which indicates a poor prognosis. (3) In the orange arrow approach, CSCs or re‐differentiated cancer cells migrate to the target organ, as CSCs or re‐differentiated cancer cells have a strong Mutation X, regardless of the status of Mutation Y. They can adapt to the microenvironment of the target organ and proliferate rapidly, expressing a synchronous metastasis pattern, which indicates a poor prognosis

FIGURE 3

The evolution of CRC according to our “conversion‐deterioration‐double mutation” theory. For CMS1, CMS2, CMS3, CMS4, and mixed or indeterminate tumors, each of them can match a position in our model. In this figure, the solid line indicates a high possibility. The dotted line indicates a low possibility. This figure showed that CMS4 tumor and CMS3 tumor are the final stages of tumor progression. (1) The orange arrow showed how CMS1 tumors arise. Normal colorectal epithelial cells undergo a loss of function mutation of MMR genes and become CRC cells. (2) The green arrows showed how CMS2 tumors arise. Normal colorectal epithelial cells undergo an APC gene mutation and become colorectal adenoma cells. Then the colorectal adenoma cells undergo a p53 mutation to become CRC cells. (3) The blue arrow showed how CMS2 tumors convert into CMS3 tumors. The CMS2 cancer cells are differentiated into CSCs, and CSCs re‐differentiated and produce re‐differentiated cancer cells which have a different metabolic pattern. (4) The red arrow showed how CMS4 tumors arise. The normal stem cells in colorectal epithelium directly convert into CSCS