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Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma
A B Glick1, M M Lee, N Darwiche
1Laboratory of Cellular Carcinogenesis and Tumor Promotion, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland 20892.
Abstract:
To study the contribution of autocrine and paracrine TGF-beta 1 to tumor progression in a well-defined system of multistage carcinogenesis, keratinocytes with a targeted deletion of the TGF-beta 1 gene were initiated in vitro with the v-rasHa oncogene and their in vivo tumorigenic properties were determined by skin grafting initiated cells onto athymic mice in combination with either wild-type or null dermal fibroblasts. Grafts of v-rasHa-initiated null keratinocytes progressed rapidly to multifocal squamous cell carcinomas within dysplastic papillomas irrespective of the fibroblast genotype, whereas the initiated control genotypes formed well-differentiated papillomas. Malignant progression was not associated with mutations in the c-rasHa gene, alterations in p53 protein, or loss of responsiveness to TGF-beta 1. The tumor cell labeling index was elevated in grafts of initiated null keratinocytes with wild-type fibroblasts compared to tumors of other genotypes. However, labeling index in all tumors was reduced when TGF-beta 1 null fibroblasts formed the stroma. The null tumor cells could not accumulate TGF-beta 1 from the host, but grafts of uninitiated null keratinocytes, which formed a normal epidermis, became TGF-beta 1 positive even though they did not express TGF-beta 1 mRNA. These results demonstrate that autocrine TGF-beta 1 suppresses the frequency and rate of malignant progression, and that autocrine and paracrine TGF-beta 1 can have opposing effects on tumor cell proliferation. The lack of paracrine inhibition of tumor cell progression appears to result from the inability of tumor cells to localize host-derived TGF-beta 1 by a mechanism that operates in normal cells.
Insights
Autocrine transforming growth factor-beta 1 (TGF-β1) suppresses cancer progression. However, paracrine TGF-β1 can promote tumor cell proliferation, with tumor cells unable to utilize host TGF-β1.
Area of Science:
- Oncology
- Cell Biology
- Carcinogenesis
Background:
- Transforming growth factor-beta 1 (TGF-β1) plays complex roles in cancer.
- Understanding autocrine and paracrine TGF-β1 contributions to tumor progression is crucial.
Purpose of the Study:
- To investigate the distinct roles of autocrine and paracrine TGF-β1 in multistage carcinogenesis.
- To elucidate the mechanisms underlying TGF-β1's influence on tumor development and cell proliferation.
Main Methods:
- Utilized a well-defined multistage carcinogenesis system with TGF-β1 gene-deleted keratinocytes.
- Assessed in vivo tumorigenic properties via skin grafting onto athymic mice with varying fibroblast genotypes (wild-type or null).
- Analyzed tumor progression, cell proliferation (labeling index), and molecular alterations (c-rasHa, p53).
Main Results:
- TGF-β1 deletion in keratinocytes led to rapid progression to squamous cell carcinomas.
- Autocrine TGF-β1 suppressed tumor frequency and progression rate.
- Paracrine TGF-β1 from wild-type fibroblasts increased tumor cell proliferation, while TGF-β1 null fibroblasts reduced it.
- Tumor cells could not effectively utilize host-derived TGF-β1, unlike normal cells.
Conclusions:
- Autocrine TGF-β1 acts as a tumor suppressor in early carcinogenesis.
- Autocrine and paracrine TGF-β1 exert opposing effects on tumor cell proliferation.
- Impaired utilization of host-derived TGF-β1 contributes to uncontrolled tumor progression.