Cancer cells alter their metabolism for the production of precursors of macromolecules. However, the control mechanisms underlying this reprogramming are poorly understood. Here we show that metabolic reprogramming of colorectal cancer is caused chiefly by aberrant MYC expression. Multiomics-based analyses of paired normal and tumor tissues from 275 patients with colorectal cancer revealed that metabolic alterations occur at the adenoma stage of carcinogenesis, in a manner not associated with specific gene mutations involved in colorectal carcinogenesis. MYC expression induced at least 215 metabolic reactions by changing the expression levels of 121 metabolic genes and 39 transporter genes. Further, MYC negatively regulated the expression of genes involved in mitochondrial biogenesis and maintenance but positively regulated genes involved in DNA and histone methylation. Knockdown of MYC in colorectal cancer cells reset the altered metabolism and suppressed cell growth. Moreover, inhibition of MYC target pyrimidine synthesis genes such as CAD, UMPS, and CTPS blocked cell growth, and thus are potential targets for colorectal cancer therapy.ne of the prominent characteristics of rapidly growing tumor cells is their capacity to sustain high rates of glycolysis for ATP generation irrespective of oxygen availability, termed the Warburg effect (1). Recent studies have shown that cancer cells shift metabolic pathways to facilitate the uptake and incorporation of abundant nutrients, such as glucose and glutamine (2, 3), into cell building blocks, such as nucleotides, amino acids, and lipids, that are essential for highly proliferating cells (4). This seems to be a universal characteristic of highly malignant tumors (5), independent of their carcinogenetic origin (6). Understanding how cancer cells reprogram metabolism can stimulate the development of new approaches in cancer therapy.Although there is now substantial information about how these pathways are regulated, most existing studies on cancer metabolism have used in vitro cell lines. In addition to genetic and epigenetic alterations, altered tumor microenvironment (e.g., blood flow, oxygen and nutrient supply, pH distribution, redox state, and inflammation) plays a profound role in modulating tumor cell metabolism (7-9). Therefore, a systematic characterization of in vivo metabolic pathways was deemed necessary to understand how metabolic phenotypes are regulated in intact human tumors.Here we applied multiomics-based approaches [i.e., metabolomics, target sequencing of cancer-related genes, transcriptomics, and methylated DNA immunoprecipitation sequencing (MeDIPseq)] to paired normal and tumor tissues obtained from 275 patients with colorectal cancer (CRC) and uncovered the details of which factors contributed, and when they contributed, to metabolic reprogramming in colorectal cancer. The results were confirmed by analysis of colorectal tissue from Apc mutant mice and cancer cell lines.
The PI3K/AKT/mTOR pathway is frequently activated in various human cancers and has been considered a promising therapeutic target. Many of the positive regulators of the PI3K/AKT/mTOR axis, including the catalytic (p110α) and regulatory (p85α), of class IA PI3K, AKT, RHEB, mTOR, and eIF4E, possess oncogenic potentials, as demonstrated by transformation assays in vitro and by genetically engineered mouse models in vivo. Genetic evidences also indicate their roles in malignancies induced by activation of the upstream oncoproteins including receptor tyrosine kinases and RAS and those induced by the loss of the negative regulators of the PI3K/AKT/mTOR pathway such as PTEN, TSC1/2, LKB1, and PIPP. Possible mechanisms by which the PI3K/AKT/mTOR axis contributes to oncogenic transformation include stimulation of proliferation, survival, metabolic reprogramming, and invasion/metastasis, as well as suppression of autophagy and senescence. These phenotypic changes are mediated by eIF4E-induced translation of a subset of mRNAs and by other downstream effectors of mTORC1 including S6K, HIF-1α, PGC-1α, SREBP, and ULK1 complex.
The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates cell growth via mTOR complex 1 (mTORC1), whose activation has been implicated in many human cancers. However, mTORC1's status in gastrointestinal tumors has not been characterized thoroughly. We have found that the mTORC1 pathway is activated with increased expression of the mTOR protein in intestinal polyps of the Apc ⌬716 heterozygous mutant mouse, a model for human familial adenomatous polyposis. An 8-week treatment with RAD001 (everolimus) suppressed the mTORC1 activity in these polyps and inhibited proliferation of the adenoma cells as well as tumor angiogenesis, which significantly reduced not only the number of polyps but also their size. -Catenin knockdown in the colon cancer cell lines reduced the mTOR level and thereby inhibited the mTORC1 signaling. These results suggest that the Wnt signaling contributes to mTORC1 activation through the increased level of mTOR and that the activation plays important roles in the intestinal polyp formation and growth. Indeed, longterm RAD001 treatment significantly reduced mortality of the Apc ⌬716 mice. Thus, we propose that the mTOR inhibitors may be efficacious for therapy and prevention of colonic adenomas and cancers with Wnt signaling activation.adenoma ͉ colon cancer ͉ mammalian target of rapamycin ͉ RAD001 ͉ rapamycin
Recent reports have suggested critical roles of myeloid cells in tumor invasion and metastasis, although these findings have not led to therapeutics. Using a mouse model for liver dissemination, we show that mouse and human colon cancer cells secrete CCchemokine ligands CCL9 and CCL15, respectively, and recruit CD34 + Gr-1 − immature myeloid cells (iMCs). They express CCL9/15 receptor CCR1 and produce matrix metalloproteinases MMP2 and MMP9. Lack of the Ccr1, Mmp2, or Mmp9 gene in the host dramatically suppresses outgrowths of disseminated tumors in the liver. Importantly, CCR1 antagonist BL5923 blocks the iMC accumulation and metastatic colonization and significantly prolongs the survival of tumor-bearing mice. These results suggest that CCR1 antagonists can provide antimetastatic therapies for patients with disseminated colon cancer in the liver.C olon cancer is one of the leading causes of cancer-related deaths (1). Although most primary tumors can be resected surgically, colorectal cancer frequently spreads to the liver, which is responsible for the high mortality of the disease (2). For successful metastasis, cancer cells need to invade surrounding tissues, penetrate microvessels, survive in circulation, disseminate to distant organs, form micrometastases, and expand into macrometastases. To progress through these steps, tumor cells often acquire the capability of survival and invasion by activating metastatic signaling pathways or inactivating metastasis suppressor genes (2, 3). In addition to these cell autonomous changes, tumor stromal cells, especially bone marrow-derived myeloid cells, actively participate in early steps of the metastatic cascade in some mouse models (4). For example, tumor-associated macrophages (TAMs) promote migration and intravasation of mammary tumor cells (5, 6). Bone marrow-derived cells that express myeloid cell marker CD11b and granulocyte marker Gr-1 (CD11b + Gr-1 + ) also promote metastasis of breast cancer cells, likely through promotion of intravasation and suppression of immune responses (7). Furthermore, CD11b + myeloid cells that express vascular endothelial growth factor receptor 1 (VEGFR1) accumulate at the metastatic sites before the arrival of lung cancer and melanoma cells and foster the dissemination of the cancer cells (8). These reports suggest that bone marrow-derived myeloid cells can help cancer epithelium in early steps of metastasis. It remains to be determined whether therapeutics targeting such myeloid cells can prevent cancer metastasis (9).As a model for invasive colon cancer, we previously constructed cis-Apc +/Δ716 Smad4 +/− (Apc/Smad4) mice that develop intestinal adenocarcinomas with marked invasions by loss of Apc and Smad4 tumor suppressor genes in the intestinal epithelium (10, 11). In the Apc/Smad4 tumors, we reported that the invading cancer epithelium is associated with immature myeloid cells (iMCs) that express myeloid progenitor cell marker CD34 and CD11b (12). Because these iMCs do not express Gr-1 or VEGFR1, they belong to a different subc...
In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.
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