Increased Tumor Growth in Mice with Diet-Induced Obesity: Impact of Ovarian Hormones

Yakar, Shoshana; Núñez, Nomelí P.; Pennisi, Patricia; Brodt, Pnina; Sun, Hui; Fallavollita, Lucia; Zhao, Hong; Scavo, Louis M.; Novosyadlyy, Ruslan; Kurshan, Naamit; Stannard, Bethel; East-Palmer, Joyce; Smith, Nicole C.; Perkins, Susan N.; Fuchs-Young, Robin; Barrett, J. Carl; Hursting, Stephen D.; LeRoith, Derek

doi:10.1210/en.2006-0311

Cited by 131 publications

(125 citation statements)

References 53 publications

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“…M-27 IGFÀIR cells were generated by stable transfection of M-27 cells with a full-length hIGF-IR cDNA resulting in the acquisition of a liver-metastasizing potential (Brodt et al, 2001). The origin, properties and maintenance of murine MC-38 colon adenocarcinoma cells were described previously (Yakar et al, 2006;Wang et al, 2009). All cells were maintained as frozen stocks and cultured for up to 4 weeks in RPMI medium supplemented with 10% fetal calf serum and antibiotics before the analyses described.…”

Section: Cellsmentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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The liver is a major site of metastasis for human malignancies, yet the factors that regulate tumor cell survival and growth in this organ remain elusive. Previously, we reported that M-27 IGFÀIR murine lung carcinoma cells with ectopic insulin-like growth factor-1 (IGF-I) receptor overexpression acquired a site-specific, liver-metastasizing potential. Gene expression profiling and subsequent RNA and protein analyses revealed that this was associated with major changes to the expression of extracellular matrix (ECM) protein-encoding genes including type III, IV and XVIII collagen genes, and these changes were also observed in the respective tumors in vivo. Because type IV collagen was the most prominently altered ECM protein in this model, we further analyzed its functional relevance to liver metastasis. M-27 cells stably overexpressing type IV collagen a1 and a2 chains were generated and their growth and metastatic properties investigated. We found that these cells acquired a site-selective growth advantage in the liver and this was associated with cell rescue from anoikis in a collagen IV/a2 integrin/FAK-dependent manner and increased responsiveness to IGF-I. Conversely, collagen IV or focal adhesion kinase (FAK) silencing by smallinterfering RNA in highly metastatic tumor cells enhanced anoikis and decreased liver metastases formation. Moreover, analysis of human surgical specimens revealed uniformly high collagen IV expression in 65/65 hepatic metastases analyzed, regardless of tissue of origin, whereas it was variable and generally low in 50/50 primary colorectal carcinoma specimens examined. The results suggest that collagen IV-conveyed signals are essential cues for liver metastasis in diverse tumor types and identify mediators of collagen IV signaling as potential therapeutic targets in the management of hepatic metastases.

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Section: Cellsmentioning

confidence: 99%

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

et al. 2011

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“…12 In vitro studies have provided evidence that leptin modulates the proliferation of colon adenocarcinoma cells LS174T and HM7. 13 The binding of insulin to its receptor phosphorylates insulin receptor substrates IRS-1 and IRS1/4, stimulating the downstream signaling. 14 IRS-1 activation stimulates the RAS/ RAF/MEK/ERK (extracellular signal-regulated kinase) pathway to induce cell proliferation.…”

Section: Introductionmentioning

confidence: 99%

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

et al. 2011

Int J Obes

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Objective: Studies have indicated that obesity is associated with a higher risk of colorectal cancer. This study was performed to determine the effect of diet-induced obesity on the formation of azoxymethane (AOM)/dextran sodium sulfate (DSS)-induced colon tumors and to identify adiposity-related mechanisms. Methods: Male A/J mice were placed on either a high-fat diet (HFD; 45% of total calories from fat) or a normal diet (ND; 15% of calories from fat) for 12 weeks. To induce colon tumors, AOM was administered at a dose of 10 mg/kg body weight, followed by two cycles of DSS supply. Results: Study results indicated that the HFD group had twofold higher numbers of colonic tumors, as compared with the ND group. The HFD group also had significantly increased body weight and epididymal fat weight, which were associated with increases of serum insulin, insulin-like growth factor-1, leptin, epididymal fat pad leptin mRNA and colonic leptin receptor (Ob-R) mRNA. Animals on HFD showed higher expressions of Ob-R, insulin receptor, phosphorylated Akt, phosphorylated extracellular signal-regulated kinases, Bcl-xL and Cyclin D1 proteins in the colon. Conclusion:The results suggest that HFD-induced obesity facilitates colon tumor formation, possibly by regulating downstream targets of circulating adiposity-related factors via receptor-mediated signaling of the phosphatidylinositol 3-kinase/Akt pathway.

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“…Accumulating evidence in experimental animals support these data and indicate that normal colonic epithelial cells as well as CRC cells proliferate more rapidly in obese animals and in mice fed a hypercaloric diet (30,31). Moreover, tumor development and size is increased after subcutaneous injection of CRC cells in obese compared to non-obese mice (32). By contrast, animal studies have demonstrated that calorie restriction strongly inhibits cancer and slows tumor growth (33).…”

Section: Obesity and Colorectal Cancer Riskmentioning

confidence: 93%

Translational approaches to addressing complex genetic pathways in colorectal cancer

Early

Fontana

Davidson

2008

Translational Research

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Colorectal cancer (CRC) is among the most prevalent cancers worldwide and represents a major public health challenge in the developed world. From the perspective of translational investigation, scientists have enormous opportunity to elucidate the molecular genetic mechanisms contributing to CRC pathogenesis since the majority of cancers arise from adenomatous precursor lesions. The process of adenoma growth and transformation is accompanied by cumulative mutations in dominant genetic pathways that confer a growth advantage. While this developmental process permits interrogation of informative pathways prior to the development of cancer, only a minority of adenomas progress to CRC. Accordingly, a major challenge for clinical translational investigators is to identify the molecular signatures that indicate increased likelihood for adenoma progression. By corollary, these molecular signatures include mutations in high penetrance alleles, including the Adenomatous Polyposis Coli (APC) gene as well as other alleles in the Wnt/β-catenin signaling pathway that specify increased genetic susceptibility to CRC. Interactions between these high penetrance alleles and other modifier genes as well as with environmental factors are of particular importance in understanding the complex network of events leading to CRC. This brief review will highlight three areas where important questions concerning genetic and environmental risk factors have fueled translational investigation into possible pathways leading to CRC.There have been substantial advances in the last two decades in our understanding of the molecular pathways that lead to colorectal cancer (CRC), the results of research that demonstrated the role of mutational activation of oncogenes coupled with loss of function of tumor suppressor genes in a model that advanced the concept of finite, but cumulative mutational events (summarized in (1)). These studies in preclinical, animal models as well as cell-based models, clinical observational and randomized studies in humans have led to a more complete understanding of the role of both environmental and genetic factors in CRC pathogenesis.One tangible result of this expanded scientific foundation is an emerging consensus that familial or inherited factors play an increasingly relevant role in our approach to patients with CRC(2). Examples of dominant genetic pathways include those governed by Adenomatous Polyposis Coli (APC) tumor suppressor gene, and also the microsatellite instability pathway 4 To whom communication should be directed

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Increased Tumor Growth in Mice with Diet-Induced Obesity: Impact of Ovarian Hormones

Cited by 131 publications

References 53 publications

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Type IV collagen-initiated signals provide survival and growth cues required for liver metastasis

Effects of diet-induced obesity on colitis-associated colon tumor formation in A/J mice

Translational approaches to addressing complex genetic pathways in colorectal cancer

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