Decreased metastatic phenotype in cells resistant to aminolevulinic acid-photodynamic therapy
Adriana Casas1, Gabriela Di Venosa, Silvia Vanzulli
1Centro de Investigaciones sobre Porfirinas y Porfirias, CONICET and Hospital de Clínicas José de San Martín, University of Buenos Aires, 1056 Ciudad de Buenos Aires, Córdoba 2351 1er subsuelo, CP 1120AAF, Buenos Aires, Argentina. adriana@qb.fcen.uba.ar
Abstract:
Photodynamic therapy (PDT) is a novel cancer treatment utilising a photosensitiser, visible light and oxygen. PDT often leaves a significant number of surviving tumour cells. In a previous work, we isolated and studied two PDT resistant clones derived from the mammary adenocarcinoma LM3 line (Int. J. Oncol. 29 (2006) 397-405). The isolated Clon 4 and Clon 8 exhibited a more fibroblastic, dendritic pattern and were larger than the parentals. In the present work we studied the metastatic potential of the two clones in comparison with LM3. We found that 100% of LM3 invaded Matrigel, whereas only 19+/-6% and 24+/-7% of Clon 4 and Clon 8 cells invaded. In addition, 100% of LM3 cells migrated towards a chemotactic stimulus whereas 38+/-8% and 73+/-10% of Clones 4 and 8, respectively, were able to migrate. In vivo, 100% of the LM3 injected mice developed spontaneous lung metastasis, whereas none of the Clon 8 did, and only one of the mice injected with Clon 4 did. No differences were found in the proteolytic enzyme profiles among the cells. Anchorage-dependent adhesion was also impaired in vivo in the resistant clones, evidenced by the lower tumour take, latency time and growth rates, although both clones showed in vitro higher binding to collagen I without overexpression of beta1 integrin. This is the first work where the metastatic potential of cells surviving to PDT has been studied. PDT strongly affects the invasive phenotype of these cells, probably related to a higher binding to collagen. These findings may be crucial for the outcome of ALA-PDT of metastatic tumours, although further studies are needed to extrapolate the results to the clinic employing another photosensitisers and cell types.
Insights
Photodynamic therapy (PDT) resistance in cancer cells significantly reduces their metastatic potential. Surviving cells show impaired invasion and migration, suggesting PDT may impact tumor spread, especially in metastatic cancers.
Area of Science:
- Oncology
- Cancer Biology
- Photodynamic Therapy Research
Background:
- Photodynamic therapy (PDT) is a cancer treatment using photosensitizers, light, and oxygen.
- PDT can leave surviving tumor cells that may possess altered characteristics.
- Previous work identified two PDT-resistant clones (Clon 4 and Clon 8) from the LM3 mammary adenocarcinoma line.
Purpose of the Study:
- To investigate the metastatic potential of PDT-resistant cancer cell clones.
- To compare the invasive and migratory capabilities of PDT-resistant clones with their parental cell line.
- To assess the in vivo metastatic behavior of PDT-resistant clones.
Main Methods:
- In vitro invasion assays using Matrigel.
- In vitro cell migration assays towards a chemotactic stimulus.
- In vivo studies involving tumor cell injection in mice to evaluate spontaneous lung metastasis.
- Analysis of proteolytic enzyme profiles and anchorage-dependent adhesion.
- In vitro binding assays to collagen I and beta1 integrin expression analysis.
Main Results:
- PDT-resistant clones (Clon 4 and Clon 8) exhibited significantly reduced Matrigel invasion compared to parental LM3 cells.
- Migration towards chemotactic stimuli was lower in Clon 4 and Clon 8 compared to LM3 cells.
- In vivo, LM3 cells formed lung metastases in 100% of mice, while Clon 8 cells formed none, and only one mouse injected with Clon 4 developed metastasis.
- Anchorage-dependent adhesion was impaired in vivo for resistant clones, with lower tumor take, latency, and growth rates.
- Resistant clones showed increased in vitro binding to collagen I without beta1 integrin overexpression.
Conclusions:
- This study is the first to examine the metastatic potential of cells surviving PDT.
- PDT significantly impacts the invasive phenotype of surviving cancer cells, potentially linked to altered collagen binding.
- These findings suggest PDT may reduce the metastatic capacity of cancer cells, with implications for treating metastatic tumors, though further research is needed.
