Differential gene expression during colon-to-lung metastasis

Abstract

Abstract. Primary tumors in certain metastatic cases have potential dissemination mechanisms. However, they often lack the potential to colonize distant microenvironments, and consequently the disseminated cancer cells enter into a state of latency which can last for years. In order to investigate the metastatic colonization potential at the gene expression level, we compared such primary tumors with their matching, actively proliferating metastatic tumors. Six pairs of colonto-lung metachronous tumor samples were examined for the expression levels of 84 well-known metastatic genes using the quantitative RT-PCR-based PCR Array technology. The unsupervised hierarchical clustering of all 12 samples together, resulted in the formation of one closely related cluster by the primary tumors, but highly diversified ones by the metastatic tumors. A pair-wise comparison of the matching primarymetastatic tumors showed that different groups of genes were activated in the lung metastases. Therefore we charted specific genes involved in the genetic diversification processes. A number of these genes showed similar differential expression (ΔCt) patterns in all the patients. These were the cancer cell-, the microenvironment-and the stem cell-specific gene groups. In conclusion, the results suggest that the primary colorectal cancer cells are diversified as regards colonization of the lung, which could explain why the effective therapies for primary colorectal cancers are often not appropriate for controling the growth of pulmonary metastases. IntroductionMetastasis can be viewed as two consecutive cellular processes: Dissemination of the cancer cells from the primary tumor to distant sites, and colonization of the disseminated cancer cells of microscopic size into full-blown metastatic malignancies (1,2). When disseminated to a distant microenvironment, most cancer cells can no longer grow in the alien microenvironment, and thus enter into a state of latency which can last for months or years until they discover new growth mechanisms (3-5). Understanding how the micrometastases come out of their latent state to colonize the distant organ is of prime interest, as it could lead us to a therapeutic means of controling the process. However, such studies are generally not practically feasible, as metastasectomies are rarely performed, and even in those rare cases, the invasiveness of the matching primary tumors often decreases during the latent years.However, recent trends of aggressive metastasectomy, particularly of lung metastases of colorectal origin (6,7), could shed a light on this problem. Surgical resection of metastatic tumors is usually performed when, i) recurrence is not detected in the primary site, ii) complete surgical removal of the metastases is feasible, iii) there is no evidence of metastasis in other organs other than the lung, and iv) the patient can tolerate the surgery (6). The tumors removed thereby, are chronologically separated during the latent periods, and genetic differences (5,8) reflect the changes in t...

A core program of gene expression characterizes cancer metastases

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“…Despite variation from tumor heterogeneity, clonal evolution and host factors, consistent genetic adjustments are required within the tumor cells to complete the process of metastasis. Although research over the past fifteen years has identified some genes, the expression of which is associated with cancer dissemination to specific sites [ 30 – 32 , 17 , 18 ], gene regulation maps that reflect organ specificity in cancer spread are still lacking. Here we expand on earlier microarray analyses [ 33 , 34 ] and investigate metastasis-specificity in gene expression signatures from various primary tumors, their metastases, and host tissue in target sites to identify genetically encoded programs that distinguish the disseminated growths.…”

MiR expression profiles of paired primary colorectal cancer and metastases by next-generation sequencing

“…In previous studies, conflicting results of the genomic characteristics of both primary CRC (pCRC) and metastases from the same patients were found, varying from an almost identical make-up 8 , 9 , 10 , 11 to clear differences. 12 , 13 …”

Prognostic factors in pulmonary metastasectomy: spotlight on molecular and radiological markers

“…The up-regulation of CD44 seems to play an important role in the homing of tumour cells to metastatic sites [25]. An increased expression of the CD44 gene in pulmonary metastases compared with corresponding primary CRC was found in a study by Kim et al [26]. In a subsequent study, CD44 variant 9 expression was found in 88% of primary CRC with consecutive pulmonary dissemination, compared with 42% in patients without pulmonary dissemination.…”