Abstract
Chemotherapy is still widely used as a coadjutant in gastric cancer when surgery is not possible or in presence of metastasis. During tumor evolution, gatekeeper mutations provide a selective growth advantage to a subpopulation of cancer cells that become resistant to chemotherapy. When this phenomenon happens, patients experience tumor recurrence and treatment failure. Even if many chemoresistance mechanisms are known, such as expression of ATP-binding cassette (ABC) transporters, aldehyde dehydrogenase (ALDH1) activity and activation of peculiar intracellular signaling pathways, a common and universal marker for chemoresistant cancer cells has not been identified yet. In this study we subjected the gastric cancer cell line AGS to chronic exposure of 5-fluorouracil, cisplatin or paclitaxel, thus selecting cell subpopulations showing resistance to the different drugs. Such cells showed biological changes; among them, we observed that the acquired chemoresistance to 5-fluorouracil induced an endothelial-like phenotype and increased the capacity to form vessel-like structures. We identified the upregulation of thymidine phosphorylase (TYMP), which is one of the most commonly reported mutated genes leading to 5-fluorouracil resistance, as the cause of such enhanced vasculogenic ability.
Highlights
Gastric Cancer (GC) is to date the sixth malignancy for incidence (5.6%) and the fourth for mortality (7.7%) globally, behind lung (11.4% incidence; 18.0% mortality), breast (11.7%; 6.9%), prostate (7.3%; 3.8%), colorectal (10.0%; 9.4%), liver (4.7%; 8.3%) carcinomas and non-melanoma skin cancers (6.2%; 0.6%) [1]
We evaluated the effects at the cellular and molecular level of the chronic exposure of the AGS cell line to 5-fluorouracil (5-FU), cisplatin (CIS) and paclitaxel (TAX), three chemotherapeutic agents commonly used in GC treatment
Low-density AGS cells were initially treated for 24 h with 5-FU (3 μM) or CIS (2 μM) or TAX (1 nM) and plates were rinsed and cells were allowed to grow in drug-free fresh complete media until reaching sub-confluence, replenishing media every 2–3 days
Summary
Gastric Cancer (GC) is to date the sixth malignancy for incidence (5.6%) and the fourth for mortality (7.7%) globally, behind lung (11.4% incidence; 18.0% mortality), breast (11.7%; 6.9%), prostate (7.3%; 3.8%), colorectal (10.0%; 9.4%), liver (4.7%; 8.3%) carcinomas and non-melanoma skin cancers (6.2%; 0.6%) [1]. While angiogenesis is commonly described as a complex mechanism including the remodeling of extracellular matrix, the formation of the Tip-Stalk cell hierarchy and the involvement of pericytes, VM is typically characterized by highly perfused blood lacunae not surrounded by endothelium but composed of tumor cells with significant deposition of matrix proteins and it is often associated with highly invasive and metastatic tumors, frequently paired with a poor prognosis [8]. There are other two processes described for the formation of new blood vessels: the segmentation of a pre-existing blood vessel through the involvement of the interstitial columnar structures, commonly referred to as intussusceptive angiogenesis [11] and the vessel co-option, frequently observed in many malignancies, which is the migration of tumor cells along the walls of a blood vessel to generate a new complex structure [12]. We aimed at the investigation of mechanisms involved in the chemoresistance of AGS cells, focusing in particular on the capacity of cancer cells to form a new vascular network. 5FU-resistant cells, which demonstrated, among the analyzed phenotypes, a significant upregulation of the thymidine phosphorylase gene (TYMP), were capable to form complex vessels via the expression of typical angiogenesis markers
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