Colorectal neoplasia (CRN) and colorectal cancer (CRC) still pose major challenges concerning etiology, early diagnosis, prognosis, and treatment. Deaths due to colorectal cancer rank among the highest cancer related mortalities [1
]. Recently, epithelial transporter dysfunctions of the colon have attracted attention in relation to development of CRN and CRC [2
]. The colon has a molecular excretory system build to excrete xenobiotics, toxins and waste metabolites in parallel with excretory systems found in kidney and liver [4
]. Many molecular transporters are conceived to take part in this excretory paradigm of the colon. Several of these transporters are also considered important for controlling the level of intracellular signaling molecules [5
]. Selective basolateral and apical molecular transporters of normal colonic epithelial cells are furthermore believed to be important in maintenance of a healthy micro-environment, while dysfunction of these excretory mechanisms is suspected to cause a cytotoxic and potentially oncogenic milieu [6
]. Special attention has been paid to members of the large ATP-binding cassette family (ABC-transporters) [2
]. An association of these transporters to cancer is well established with respect to response to anti-cancer treatment and prognostics [4
]. Studies on a possible connection to cancer development by other types of transporters such as the organic anion transporting polypeptides (OATPs) are now being initiated as well [5
]. However, the function and build-up of the colonic excretory system including its transporters are yet insufficiently characterized.
Recently, second messengers in form of cyclic nucleotides (cNTs) such as cAMP and cGMP have turned out as shared substrates for some OATP- and ABC-transporters [11
]. Both transporter families have members characterized by substrate promiscuity and overlap [13
]. The importance of cellular import and export of cNTs is still debated, though gradually accepted as a mean to regulate intracellular levels of these signaling molecules [11
]. cNT influx is thought to occur by transporter OATP4C1, newly reported to influx cAMP over the basolateral membrane of kidney tubule cells and also present in the human colon [11
]. Known mediators of cNT-efflux, as ABCC4, ABCC5 and ABCC8, are expressed in colonic tissue together with other ABC-transporters as established by rt-qPCR [15
]. Meanwhile, it is unknown which transporters are involved in the turnover of cNTs in colon epithelial cells and which colonic transporters are involved in functions possibly related to cancer progression and prognostics [14
It has become easy to assess transporter function and secretion in in vitro
human colon epithelium by means of the mini-Ussing air suction (MUAS)-chamber technique [17
]. And, since colonic secretion is induced by cAMP, which is likely transported basolaterally to the interior by presence of the OATP4C1-influxer, we have taken advantage of this transfer to study the effect of externally applied cNTs on the induction of colonic secretion and possible excretion.
The overall aim of this study had two objectives. One objective was to functionally characterize the excretory system of human colon and to investigate whether alterations or dysfunctions in this molecular excretory system is associated with CRN and CRC pathogenesis. The second objective was an initial characterization of the turnover processes of second messenger cAMP, related to transporters in human colonic mucosa.
We conclude that transporters as OATP1C1, OATP4A1, OATP4C1 seem to be involved in the excretory system of human colon. ABCC4 is also involved but from an endoplasmic-Golgi complex location, while OATP2B1 is indirectly related to the excretory system. ABCC5 might be directly involved in the turnover of intracellular cAMP. Colonic epithelium from CRN-patients had lower transport or sensitivity to cyclic nucleotides and an increased expression of two PGE2-transporters, OATP2B1 and OATP4A1; however it is premature to draw firm conclusions based on this latter observation.