Medical Hypotheses I

Medical Hypohh-sar(1992) 39.366366 0L.Jn@mGroupIJKLtd1992

The Detachment

Cascade During Metastasis

C. H. VAN ASWEGEN and D. J. DU PLESSIS Department Department

of Urology, University of Pretoria, Pretoria 0001, South Africa (Correspondence to CHVA, of Urology, HF Verwoerd Hospital, Private Bag xl 69, Pretoria 0001, South Africa).

Abstract-The cause of detachment of tumour cells during metastasis is still one of the most intriguing questions of tumour propagation. A hypothesis is suggested herein for lysis of extracellular matrix that could ultimately lead to the detachment and spreading of malignant cells. According to this theory a certain optimal estrogen level initiates a series of enzymatic activations that culminate in detachment and spreading of tumour cells.

Cancer is one of the most common and troublesome health care problems in modem living. Little is known about the natural history and clinical causes of the disease and numerous questions remain unanswered. The metastatic process of cancer propagation can be summarized as follows (1): 1) After progressive growth of neoplastic cells; 2) extensive vascularization and; 3) local invasion of the host stroma by some of the tumour cells; 4) detachment and embolism ensue, followed by; 5) cell entrapment in the capillary beds of the organs and finally; 6) extravasion and; 7) proliferation within the parenchyma. One of these events, namely detachment of cells, implies breakdown of the extracellular matrix, allowing spreading of tumour cells to occur. We hypothesize that a cascade of mechanisms, initiated by estrogen, is responsible for this breakdown of the extracellular matrix, as schematically illustrated in the Figure. It is well known that estrogens are; possible carcinogens (2, 3), biphasic (4, 5), and are, at least, cofactors in carcinogenesis (6-17). On this basis we hypothesize that an optimal estrogen concentration may well initiate the detachment cascade and could exDate received Date accepted

18 June 1992 11 July 1992




I COLLACENASE 1 COLLAGEN 1 DETACHMENT OF CELLS Fig. Schematic diagram of the putative detachment cascade mechanisms resulting in breakdown of the extracellular matrix.

plain the unidentified role of estrogens in the prostate




gland (18). Although it has been reported that some cancer tissues do not contain estrogen receptors, we consider that estrogen receptors are indeed present, but that these receptors are either occupied with estrogens (19) or are masked by sialic acid (20) at the time of assay. Estrogens, which are known to stimulate DNA and mRNA synthesis (21, 22), have a bifunctional effect on prostaglandins and peptide growth factors. Estrogen stimulates the prostaglandin F-type (23, 24) and E-type (25) which in turn stimulate urokinase (UK) activity (26). The second function of estrogens is to stimulate the production of UK via increased production of fibroblast growth factor (FGF), epidermal growth factor (EGF) and platelet derived growth facto1 (PDGF)(27-31). These growth factors are responsible for increasing the levels of UK (32-35). Pro-UK may be activated by: 1) autocatalytic intrinsic activation; 2) activation by serine proteases (plasmin, kallikrein, Factor xiii a) and/or, 3) activation by cysteine proteases (cathepsin B and L) (36). Increased UK levels and activity have been reported with various cancers (37-41) as well as a correlation between UK production and metastasis (36, 40,42, 43). Urokinase in its turn, activates collagenase by hydrolyzing plasminogen to plasmin which then activates latent collagenase (33,44,45) that degrades fibrillar collagen or basement membrane collagen (33). Plasmin also degrades both fibronectin and laminin (33). Collectively, these degradation processes lead to lysis of the extracellular matrix and metastasis of the neoplastic cells. The detachment of tumour cells is obviously a complex process, involving numerous interactions. Thus, whilst we admit that this hypothesis must be an over simplification of the real process, it does, nonetheless, illustrate a possible orchestration of estrogens with the relevant enzymes in the detachment cascade of tumour cells.


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The detachment cascade during metastasis.

The cause of detachment of tumour cells during metastasis is still one of the most intriguing questions of tumour propagation. A hypothesis is suggest...
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