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1.
Figure 4

Figure 4. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Ki67 immunostaining in the KVcTT vs. AVcTT neoplasms reveals significantly increased proliferation in the KVcTT tumors compared to the AVcTT tumors. A–B. Representative examples of tumors from the AVcTT mice (100x and 200X). C–D. Representative examples of tumors from the KVcTT mice (100X and 200X).

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
2.
Figure 1

Figure 1. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Photomicrographs of representative examples of distal colon epithelium from the KTT, KVcTwt/wt, and KVcTT mice (age: 20 weeks). A,C,E.: H&E stained sections reveal increased goblet cells and crypt length in the KVcTwt/wt and KVcTT mice compared to the KTT mice. B, D, F.: Ki67 immunostaining of the KTT, KVcTwt/wt, and KVcTT mice reveals more Ki67 labeled cells in the KVcTwt/wt and KVcTT mice compared to the KTT mice. (magnification 100×)

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
3.
Figure 3

Figure 3. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Expression of phosphorylated ERK1/2 (pThr202/Tyr204), total ERK1/2, phosphorylated AKT (pSer473), and total AKT in the normal intestinal mucosa of the KTT, KVcTT, and KVcTwt/wt mice and in the intestinal neoplasms of the KVcTT, AVcTT and ATT mice. Phosphorylated ERK1/2 is present in the adenocarcinomas (n=5) and mucosa (n=3) of KVcTT mice as well as in KVcTwt/wt epithelium (n=3). Phosphorylated ERK1/2 is present in approximately 60–70% of the neoplasms (N=9) in AVcTT and ATT mice regardless of whether Tgfbr2 is inactivated. Similarly, AKT phosphorylation is present in 40–100% of the tumors in the mouse models, and is present in the majority of the normal mucosa samples of the KTT, KVcTwt/wt, and KVcTT mice.

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
4.
Figure 5

Figure 5. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Immunoblotting of protein lysates extracted from the normal intestinal mucosa from the KTT, KVcTT, and KVcTwt/wt mice and neoplasms from the KVcTT, AVcTT, and ATT mice for p15, p21, cyclin D1 and cdk4. The expression of p15 is reduced in the tumors from the KVcTT mice compared to the normal mucosa and to the AVcTT and ATT tumors. Furthermore, p21 expression is the same or decreased in the KVcTT tumors compared to the normal mucosa and is substantially less than the majority of the AVcTT and ATT tumors. Cyclin D1 and cdk4 expression is increased in all the tumors when compared to the normal mucosa. The “X” indicates that no protein lysate was available from this sample to perform this study. Actin was used to control for protein loading.

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
5.
Figure 7

Figure 7. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Metastatic tumors in the Tgfbr2IEKO; LSL-KrasG12D/wt (KVcTT) mouse. A. Gross appearance of enlarged lymph nodes that were shown to contain metastatic tumor. The enlarged lymph nodes are indicated by arrows. B. Photomicrograph of H&E stained lymph node metastasis (100X) C. Photomicrograph of H&E stained lung metastasis (100X). D. Cytokeratin immunostaining of metastatic lesions in the lymph node (100X, insert 400X). E. Results of PCR-based assays demonstrating the recombination of the Tgfbr2E2flx allele in representative lung metastatic tumors (#1 and #2), and mesenteric lymph node (LN #3a and #3b) metastases. The positive and negative control DNA samples are from an AVcTT epithelial cell line and “normal” mesenteric lymph nodes from an age-matched KVcTT mouse that did not have grossly evident metastatic disease.

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
6.
Figure 2

Figure 2. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

A. B H&E stained tissue sections from tumors arising in the small intestine (A.) and colon (B.) (100x magnification). The tumors display marked desmoplasia and mucinous features, including signet ring cells and mucin lakes (arrow and asterisk, respectively). C, D.. β-catenin immunostaining of the normal epithelium (C. colon, D. small intestine) in the KVcTT mice reveals cytoplasmic membrane distribution, as expected. E, F. p53 immunostaining in normal intestinal epithelium (E. colon, F. small intestine) in the KVcTT mice reveals occasional cells with nuclear staining in the base and luminal surface of the epithelium in the colon and small intestine with the majority of cells showing no staining. G. β-catenin cellular localization in the neoplasms arising in the KVcTT mice. Immunostaining for β-catenin reveals that <10% of the KVcTT tumors show nuclear β-catenin {compared to 80% of the AVcTT tumors (data not shown)}. (Arrow indicates neoplastic gland with β-catenin expression.) H. Representative example of p53 immunostaining of KVcTT tumor (100X respectively). Increased nuclear p53 nuclear immunoreactivity is present in the tumors. The arrow indicates cells that show nuclear p53 immunoreactvity.

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.
7.
Figure 6

Figure 6. From: TGF-? receptor inactivation and mutant Kras induce intestinal neoplasms in mice via a ?-catenin independent pathway.

Ereg and Erbb1 expression in the intestinal mucosa of the VcTT, KTT, KVcTwt/wt and KVcTT mice and in the adenocarcinomas from the KVcTT mice. A. Epiregulin (Ereg) expression measured by qRT-PCR is increased in the neoplasms compared to the normal mucosa. (**, *** Mann Whitney test, p<0.0001) B. Erbb1 (expression measured by qRT-PCR) is increased in the neoplasms compared to the normal mucosa with the statistically significant differences shown. (* p<0.05, ** p<0.01 Mann Whitney test) REU=Relative Expression Unit C. EREG expression in the HCT116 colon cancer cell line is increased by oncogenic KRAS (KRASG13D) and TGFBR2 inactivation. Quantitative RT-PCR analysis shows EREG mRNA expression is higher in parental HCT116 (KRASG13D and biallelic TGFBR2 BATRII mutations) than in HCT116 with reconstituted TGFBR2 (HCT116 + TGFBR2 2+8), with only wild-type KRAS (HKe-3), or wild-type KRAS and TGFBR2 reconstitution (HKe-3 + TGFBR2 2+8). The deletion of the mutant KRAS allele has a more pronounced effect on EREG expression than does TGFBR2 reconstitution (*p<0.01, student’s t-test), although the differences between all the groups are statistically significant including between HKe-3 and HKe-3+TGFBR2 2+8. (**p=0.03, student’s t-test) D. EREG mRNA expression is increased in the SW480 colon cancer cell line (mutant KRAS and wild-type TGFBR2) after treatment with TGF-β RI Inhibitor III (300nM) (616453; Calbiochem).

Patty Trobridge, et al. Gastroenterology. ;136(5):1680-8.e7.

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