Metastatic transcriptional pattern revealed by gene expression profiling in primary colorectal carcinoma

Abstract

Metastatic spread to the liver is the major contributor to mortality in patients with colorectal carcinoma (CRC). In order to seek for gene expression patterns associated with metastatic potential in primary CRC, we compared the transcriptional profiles of 10 radically resected primary CRCs from patients who did not develop distant metastases within a 5-year follow-up period with those of 10 primary/metastatic tumor pairs from patients with synchronous liver metastases. To focus selectively on neoplastic cells, the study was conducted on laser-microdissected bioptic tissues. Arrays of 7,864 human cDNAs were utilized. While a striking transcriptional similarity was observed between the primary tumors and their distant metastases, the nonmetastasizing primary tumors were clearly distinct from the primary/metastatic tumor pairs. Of 37 gene expression differences found between the 2 groups of primary tumors, 29 also distinguished nonmetastasizing tumors from metastases. The gene encoding for mannosyl (a-1,3-)-glycoprotein b-1,4-N-acetyl-glucosaminyl-transferase (GnT-IV) became significantly upregulated in primary/metastatic tumor pairs (p < 0.001). GnT-IV upregulation was confirmed by RT-PCR. These data support the existence of a specific transcriptional signature distinguishing primary colon adenocarcinomas with different metastatic potential, the further pursuit of which may lead to relevant clinical and therapeutic applications. ' 2005 Wiley-Liss, Inc.Key words: DNA microarray; metastasis; colorectal cancer Colorectal carcinoma (CRC) is the second leading cause of cancer deaths in developed countries.1 Metastatic spread, mostly to the liver, is the major cause of mortality in patients with this disease. Yet while the molecular events involved in the CRC adenoma-carcinoma sequence have been largely characterized, 2 little information is available on the mechanisms responsible for the metastatic phenotype. The identification in the primary tumors of molecular factors predictive of metastatic risk may have a relevant clinical impact, allowing for more personalized and effective treatment of CRC patients.Recent evidence based on gene expression profiling has shown that a metastatic fingerprint is detectable in the bulk of primary lung and breast tumors.3,4 On the other hand, no such metastatic signature has been demonstrated in CRC. A general problem related to gene expression studies in the oncologic field is the heterogeneous histology of the bioptic specimens that may contain, in addition to cancer cells, significant fractions of nonneoplastic tissue. Due to this heterogeneity, relevant changes in cancer cell gene expression may be easily overlooked.In order to seek for gene expression patterns specific to metastasis in CRC carcinoma, avoiding interference from nontumoral tissue, we combined laser microdissection of cancer cells and DNA microarray to compare the transcriptional profile of primary colon carcinomas both with that of patient-matched liver metastases and with that of a group of primary tumors of meta...

Phenotypic characterization of human colorectal cancer stem cells

“…Moreover, the CSC model could shed light on the biology of metastases and explain why, despite extensive intratumor heterogeneity, comparison of paired samples of primary tumors and autologous metastases from the same patient frequently reveals high levels of similarity (19,(22)(23)(24). This observation is very well established in CRC and spans across diverse parameters, such as tissue morphology (19,25), repertoire of somatic genetic mutations (26,27), expression of tumor-suppressor and immunomodulatory proteins (28), and overall transcriptional profile (29). Indeed, if we assume that, in each individual CRC, the differentiation pattern is controlled by the specific repertoire of genetic mutations, we can predict that if two lesions share identical genetic backgrounds and similar genetic abnormalities they will also undergo similar differentiation programs and display similar patterns of intratumor heterogeneity in the expression of differentiation markers.…”

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“…87,88 Moreover, gene expression profiles of the primary malignancy are similar to that of the metastases that arise from it. [88][89][90] However, a small amount of cells that accumulated the genetic mishaps to facilitate metastasis is not very likely to dominate the gene expression profile of the primary tumor. This implicates that those observations cannot be readily explained by the model described above that a small clone with metastatic capacity is responsible for metastatic spread of a tumor.…”