Restoration of PTEN activity decreases metastases in an orthotopic model of colon cancer

Abstract

Background Mutational loss of tumor suppressor phosphatase and tensin homologue deleted on chromosome ten (PTEN) is associated with malignant progression in many cancers including colorectal cancer (CRC). PTEN is involved in negatively regulating the Phosphatidylinositol 3-kinase (PI3K)/AKT oncogenic signaling pathway and has been implicated in the metastatic colonization process. Few in vivo models are available to study CRC metastasis. The purpose of this study was to determine the effect of restoring PTEN activity on metastases in an orthotopic murine model. Methods GFP labeled TENN, a highly metastatic human colon cancer cell line with mutational loss of PTEN gene and TENN clones (with restoration of PTEN gene) tumors were orthotopically implanted onto the colons of BALB/c nude mice and allowed to develop primary and metastatic tumors. Seven weeks post-implantation, mice were euthanized and organs extracted for examination. Results Both TENN and TENN clone cell lines demonstrated 100% primary invasion. However, compared to the parental TENN cells, which demonstrated 62% metastases to both lungs and liver, TENN clone cells showed an approximately 50% reduction in metastasis, with only 31.6% liver metastasis and no metastasis to the lungs. Conclusion Our study shows that reactivation of PTEN tumor suppressor pathway leads to a 50% reduction in CRC metastasis without affecting primary tumor formation. Importantly, PTEN restoration also changed the organotropic homing from liver and lung metastasis to liver metastasis only. This in vivo study demonstrates that PTEN might act specifically as a metastasis suppressor and thus efforts to target the PI3K/PTEN pathway are legitimate.

mir‑106a regulates cell proliferation and apoptosis of colon cancer cells through targeting the PTEN/PI3K/AKT signaling pathway

“…Loss of PTEN was positively correlated with malignant progression of CRC (15), restoration of PTEN reduced the ratio of metastases of CRC (16). Current study aimed to investigate whether there were miRNAs that targeted PTEN and regulated the progression of CRC, thus providing a therapeutic target for CRC.…”

“…Evidences demonstrated the involvement of PTEN deactivation in tumorigenesis, whose loss increased the activity of PI3K/AKT and was correlated with cell proliferation, migration, invasion and apoptosis (13,14). Moreover, another study showed that PTEN, whose loss was positively correlated with malignant progression including tumor size and TNM advanced stage, played a crucial role at early/late stages of CRC (15); meanwhile, restoration of PTEN was reported to reduce the ratio of metastases in an orthotopic model of CRC (16). Current study aimed to investigate whether there are miRNAs that could target PTEN and regulate the progression of CRC, thus providing a therapeutic target for CRC.…”

PTEN: Multiple Functions in Human Malignant Tumors

“…Interestingly, studies performed in in vivo model systems show that PTEN reactivation in a colorectal cancer (CRC) cell line exhibiting PTEN loss reduces its metastatic capability without affecting primary tumor formation. Moreover, PTEN reactivation also changed the organotropic homing from liver and lung metastasis to liver-only metastasis ( 182 ). Importantly, Razis et al have shown that PTEN levels are predictive of cetuximab efficacy in CRC models with activated EGFR signaling and wild type KRAS/BRAF status and in the presence of an intact PI3K/AKT pathway ( 48 ).…”

The role of mouse models in colorectal cancer research—The need and the importance of the orthotopic models

“…In 1987 was created an orthotopic model of CRC in mice with injection of tumor cells in the ceacum, which enabled the study of local tumor invasion as well as metastatic dissemination—it was a more patient‐like animal tumor model . The success of this model was very high, turning it into a valuable asset in the study of the CRC, and amply used, with even some adaptations as injection of tumor cells in the rectum, and even exploring microvascular patterns of the colon concerning the differences between the mesenteric and antimesenteric side…”