Transforming growth factor-β distribution in basal cell carcinomas: relationship to proliferation index

Abstract

Transforming growth factor-beta (TGF-beta) distribution in basal cell carcinomas (BCCs) was studied using polyclonal antibodies recognizing intra- (precursor) and extracellular (activated) forms (LC 1-30 and CC 1-30), and compared with an index of cell proliferation (PCNA immunoreactivity). Intracellular TGF-beta is found in suprabasal keratinocytes and the outer root sheath. Extracellular TGF-beta is largely absent from normal skin, but is abundant in the intracellular spaces of hyperplastic epidermis overlying BCCs. Twenty-five of 29 BCCs showed increased extracellular TGF-beta in the desmoplastic stroma, with intercellular staining in nine of these. Intracellular TGF-beta was present in fibroblasts and endothelial cells, although only 17 of 29 BCCs were positive, predominantly in central cells showing apparent maturation. Little correlation was seen between the degree of staining of tumour cells and the distribution of extracellular TGF-beta. PCNA immunoreactivity was greater in BCCs compared with normal epidermis in 24 of 37 cases (P = 0.005), and was concentrated on the periphery of nodular BCCs. Strongest stromal reactivity for TGF-beta and maximal PCNA index also showed a significant correlation (P = 0.023). This study demonstrated abundant TGF-beta in the active stroma around BCCs, which may account for many of the morphological and functional characteristics of this tumour, but which may be a product of stromal rather than tumour cells.

Differential patterns of placental and epithelial cadherin expression in basal cell carcinoma and in the epidermis overlying tumours

“…In addition, some of these cases also showed reduced E-CD expression. This is in line with previous observations showing several biological abnormalities, such as increased proliferative activity and abnormal expression of keratins, involucrin, transforming growth factor beta and epidermal growth factor receptor, in the epidermis adjacent to BCC (Said et al, 1984;Asada et al, 1993;Kikuchi et al, 1993;Stamp et al, 1993). It has been suggested that diffusible factors elaborated by malignant cells and/or activated dermal cells could interfere with the normal differentiation of adjacent normal cells, causing altered expression of several antigens in non-neoplastic keratinocytes adjacent to tumours (Wolf and Bystryn, 1981).…”

Targeted deletion of the TGF-beta 1 gene causes rapid progression to squamous cell carcinoma.

“…These results suggest that TGF-pI produced by stromal fibro blasts can act as a promoting stimulus for tumor growth and epidermal hyperplasia. This is supported by immunohistochemical observations that show elevated levels of stromal TGF-pi in hyperplastic conditions of the nor mal epidermis Kane et al 1990Kane et al , 1991FowHs et al 1992;Escherick et al 1993), as well as human and experimentally induced animal tumors Gomm et al 1991;Fowlis et al 1992;Stamp et al 1993;Zenklusen et al 1994). In addi tion, the ability of TGF-^l to affect tumor cell growth indirectly through actions on the stroma has been in ferred from studies in which the growth of subcutaneously injected malignant cell lines is enhanced when they express high levels of a transfected TGF-pi gene Steiner and Barrack 1992;Chang et al 1993).…”

“…Because human basal cell carcinomas (Stamp et al 1993), squamous carcinomas of the hamster oral epithe lium (Zenklusen et al 1994), and some human breast and colon cancers (Mizukami et al 1990;Gorsch et al 1992;Mizoi et al 1993) tissues as well as application to other cell types in which independence from negative regulation by TGF-pi is achieved by alternative mechanisms.…”

“…In contrast to the loss of tumor cell TGF-pl during premalignant progression, the growth factor is highly ex pressed in the stroma of mouse and human skin carci nomas (Fowlis et al 1992;Stamp et al 1993), in squa mous tumors of the mouse oral cavity (Zenklusen et al 1994), and in the dermis and epidermis after treatment of mouse skin with tumor promoters (Fowlis et al 1992;Escherick et al 1993). Furthermore, wounding, a tumorpromoting stimulus, elevates TGF-pl in the skin (Kane et al 1991), and subcutaneous injection of TGF-pi en hances skin tumor promotion (Furstenberger et al 1989), suggesting that stromal TGF-pi could have a signifi cantly different effect on tumor cell growth than auto crine TGF-pi.…”

Modulation of the IL-1 cytokine network in keratinocytes by intracellular IL-1α and IL-1 receptor antagonist

“…Neonatal foreskin keratinocytes, rather than HaCAT cells, were used in the latter study, and it is not clear whether or not their cultures were confluent. TGF-t^l is a pleitropic cytokine constitutively synthesized by keratinocytes, which is present in the intercellular space of lesional psoriatic epidermis [17], in epidermis overlying basal cell carcinomas [18] and in retinoid treated epidermis [19]. TGF-;:* inhibits keratinocyte proliferation [20], and has a range of immunosuppressive actions, including: inhibition of T cell, B cell and monocyte proliferation and effector function [21.22]; inhibition of antigen presentation by cultured but not fresh Langerhans cells [23]; and reduction in dermal microvascular endothelial cell adhesiveness for peripheral blood mononuclear cells (PBMC) [24].…”