Management of perineural invasion in sebaceous carcinoma of the eyelid.

PURPOSE: To report the occurrence and management of perineural invasion in patients with sebaceous carcinoma of the eyelid. METHODS: An ophthalmology database was searched for all patients treated for sebaceous carcinoma of the eyelid by the principal investigator between May 1999 and May 2010. The clinical records and pathology specimens of the patients with microscopic perineural invasion as an incidental finding in their eyelid surgical specimen were reviewed. RESULTS: Forty-two patients with sebaceous carcinoma of the eyelid were treated by the principal investigator during the study period. Three of them had evidence of microscopic perineural invasion in the surgical specimen. Each patient was treated with surgery with or without radiotherapy. The first patient underwent orbital exenteration and negative sentinel lymph node biopsy, subsequently developed distant metastasis, and died 20 months after exenteration. The second patient underwent resection of the tumor and positive sentinel lymph node biopsy, postoperative irradiation of the eyelid, completion neck dissection and parotidectomy for the positive sentinel lymph node, and irradiation of nodal basins; she was free of disease at last follow up (12 months after tumor resection). The third patient underwent resection of the tumor, developed regional lymph node metastasis 3 months later, underwent lymph node dissection and postoperative nodal irradiation, and was free of disease at last follow up (9 months after tumor resection). CONCLUSIONS: Perineural invasion was encountered in 7% of patients with eyelid sebaceous carcinoma. The authors' preference is to treat patients with an incidental finding of microscopic perineural invasion with postoperative adjuvant radiotherapy, ideally within 4 to 6 weeks after surgical resection of the primary eyelid tumor.

Adipose tissue derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor derived factors.

BACKGROUND: Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. METHODS: hASCs cultured under different conditions were quantified for the expression of alpha smooth muscle actin. ELISA was performed using the human TGFß1, SDF-1α and CCL5 Quantikine Kit. The invasion potential of MDAMB231 cancer cells was evaluated using a Boyden chamber with filter inserts coated with Matrigel in 24-well dishes. RESULTS: We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g. expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factor-beta 1 (TGFß1) and the differentiation of hASCs towards CAFs is dependent on TGFß1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFß1 as well as by pretreatment of the hASCs with SB431542, a TGFß1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell derived factor 1 (SDF-1) and CCL5. CONCLUSION: Our data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.

Adipose tissue-derived stem cells differentiate into carcinoma-associated fibroblast-like cells under the influence of tumor-derived factors.

Carcinoma-associated fibroblasts (CAF) are considered to contribute to tumor growth, invasion and metastasis. However, the cell type of origin remains unknown. Since human adipose tissue-derived stem cells (hASCs) are locally adjacent to breast cancer cells and might directly interact with tumor cells, we investigated whether CAFs may originate from hASCs. We demonstrated that a significant percentage of hASCs differentiated into a CAF-like myofibroblastic phenotype (e.g., expression of alpha smooth muscle actin and tenascin-C) when exposed to conditioned medium from the human breast cancer lines MDAMB231 and MCF7. The conditioned medium from MDAMB231 and MCF7 contains significant amounts of transforming growth factor-beta 1 (TGFß1) and the differentiation of hASCs towards CAFs is dependent on TGFß1 signaling via Smad3 in hASCs. The induction of CAFs can be abolished using a neutralizing antibody to TGFß1 as well as by pretreatment of the hASCs with SB431542, a TGFß1 receptor kinase inhibitor. Additionally, we found that these hASC-derived CAF-like cells exhibit functional properties of CAFs, including the ability to promote tumor cell invasion in an in vitro invasion assay, as well as increased expression of stromal-cell-derived factor 1 (SDF-1) and CCL5. Taken together, these data suggest that hASCs are a source of CAFs which play an important role in the tumor invasion.

CXCR4 receptor positive spheroid forming cells are responsible for tumor invasion in vitro.

Stem cells have been found to be involved in breast cancer growth, but the specific contribution of cancer stem cells in tumor biology, including metastasis, is still uncertain. We found that murine breast cancer cell lines 4T1, 4TO7, 167Farn and 67NR contains cancer stem cells defined by CXCR4 expression and their capability of forming spheroids in suspension culture. Importantly, we showed that CXCR4 expression is essential for tumor invasiveness because both CXCR4 neutralizing antibody and shRNA knockdown of the CXCR4 receptor significantly reduced tumor cell invasion.

Tissue-resident stem cells promote breast cancer growth and metastasis.

Mesenchymal stem cells derived from bone marrow have recently been described to localize to breast carcinomas and to integrate into the tumor-associated stroma. In the present study, we investigated whether adipose tissue-derived stem cells (ASCs) could play a role in tumor growth and invasion. Compared with bone marrow-derived cells, ASCs as tissue-resident stem cells are locally adjacent to breast cancer cells and may interact with tumor cells directly. Here, we demonstrate that ASCs cause the cancer to grow significantly faster when added to a murine breast cancer 4T1 cell line. We further show that breast cancer cells enhance the secretion of stromal cell-derived factor-1 from ASCs, which then acts in a paracrine fashion on the cancer cells to enhance their motility, invasion and metastasis. The tumor-promoting effect of ASCs was abolished by knockdown of the chemokine C-X-C receptor 4 in 4T1 tumor cells. We demonstrated that ASCs home to tumor site and promote tumor growth not only when co-injected locally but also when injected intravenously. Furthermore, we demonstrated that ASCs incorporate into tumor vessels and differentiate into endothelial cells. The tumor-promoting effect of tissue-resident stem cells was also tested and validated using a human breast cancer line MDA-MB-231 cells and human adipose tissue-derived stem cells. Our findings indicate that the interaction of local tissue-resident stem cells with tumor stem cells plays an important role in tumor growth and metastasis.

TNFalpha protects tissue resident stem cells from H2O2 induced apoptosis through a novel NF-small ka, CyrillicB p50/p50 homodimer mediated signaling pathway.

The objective of our study was to determine whether TNFalpha can protect tissue resident stem cells from hydrogen peroxide (H(2)O(2)) induced apoptosis. Apoptosis was measured via fluorescence activated flow cytometry of fluorescein-conjugated Annexin V in passage 3 human ASCs. Our data show that application of 300muM H(2)O(2) for 3h induced a high number of cells to undergo apoptosis. The number of apoptotic cells significantly decreased when cells were preincubated with TNFalpha. TNFalpha caused a rapid activation of NF-kappaB within 15min as evidenced by gel shift assay (EMSA). On further dissection of the NF-small ka, CyrillicB complex, the p50 subunit which generally forms heterodimers with p65 appears to form a p50/p50 homodimer instead of conventional p50/p65 heterodimer. This novel finding has implications for tissue regeneration and might as well be of importance for cancer cell growth and tumor progression.