Elsevier

The Lancet Oncology

Volume 3, Issue 6, June 2002, Pages 357-363
The Lancet Oncology

Review
An oncological view on the blood–testis barrier

https://doi.org/10.1016/S1470-2045(02)00776-3Get rights and content

Summary

The function of the blood–testis barrier is to protect germ cells from harmful influences; thus, it also impedes the delivery of chemotherapeutic drugs to the testis. The barrier has three components: first, a physicochemical barrier consisting of continuous capillaries, Sertoli cells in the tubular wall, connected together with narrow tight junctions, and a myoid-cell layer around the seminiferous tubule. Second, an efflux-pump barrier that contains P-glycoprotein in the luminal capillary endothelium and on the myoid-cell layer; and multidrug-resistance associated protein 1 located basolaterally on Sertoli cells. Third, an immunological barrier, consisting of Fas ligand on Sertoli cells. Inhibition of P-glycoprotein function offers the opportunity to increase the delivery of cytotoxic drugs to the testis. In the future, visualisation of function in the blood–testis barrier may also be helpful to identify groups of patients in whom testis conservation is safe or to select drugs that are less harmful to fertility

Section snippets

Clinical relevance

The delivery of cytotoxic agents to the testis seems to be worse than to most other tissues. For instance, in childhood acute lymphoblastic leukaemia, isolated testicular relapses after complete remission are reported in 1·7–13·0% of patients.1, 2 In combination with medullary and other extramedullary relapses, testicular relapses are reported in up to 17% of these patients. These relapse frequencies are almost as high as the rate of relapses in the central nervous system (CNS), which is

Functional anatomy and structural barrier

Each testis consists of about 250 lobules containing one to four seminiferous tubules (figure 2). Between the tubules, there are small groups of hormone-producing Leydig cells. The tubular wall consists of a thin tunica propria, largely consisting of myoid cells, a basal membrane, and the spermatocyte-forming epithelium, which consists of spermatogenic cells and Sertoli cells. The latter are cone-shaped cells with a complex function in the maturation of sperm cells.

At the basolateral side,

Efflux-pump barrier

The physicochemical properties of the human blood–testis barrier mainly prevent entry of large or hydrophilic molecules. Smaller or lipophilic molecules may enter the testicular tissue by transcellular transport mechanisms across cellular membranes. Although many cytotoxic compounds are small and lipophilic, in mice they do not all reach the same concentration in the testis as in other tissues.24 Efflux pumps, such as P-glycoprotein and multidrug-resistance-associated protein 1 (MRP1) play a

Immunological barrier

The immunological barrier in itself is involved neither in the delivery of drugs to the testis nor in multidrug resistance. Antibodies are prevented from entering the intratesticular environment by the physicochemical properties of the blood–testis barrier. The cellular immune response, by T lymphocytes, is impeded by the Fas-Fas-ligand system. Fas (CD95) is a membrane receptor that induces the apoptosis pathway of a cell, after binding to Fas ligand.53 Activated T lymphocytes can express Fas,

Comparison between the blood–testis barrier and the blood–brain barrier

The two barriers share many properties. There is a strong physicochemical barrier, which consists of continuous cell layers with close tight junctions, and the same efflux pumps play a part. However, there are also many differences between the two barriers. In the testis, the physicochemical barrier is maintained by three different cell layers, of which the Sertoli-cell layer is probably the most important. In the brain, however, the physicochemical-barrier function and the expression of

Visualisation of efflux-pump function in the testis

Visualisation of the function of efflux pumps in vivo has to date been achieved only for P-glycoprotein in mice and rats. So far, functional imaging of P-glycoprotein function in humans has been successful only for the blood-brain barrier.67 This technique might be translatable to the testis. P-glycoprotein function has been studied by single-photon emission computed tomography with technetium-99m-sestamibi,28 and by positron emission tomography (PET), with carbon-11-labelled verapamil. 99m

Inhibition of P-glycoprotein function

P-glycoprotein mediated efflux can be inhibited by strong substrates of the transporter, such as cyclosporin. Encouraging results with PSC 833, a cyclosporin analogue, were reported in a phase II trial in a group of patients with acute myeloid leukaemia of poor prognosis; 12 (32%) of 37 patients achieved complete remission and four achieved partial remission.70 However, a phase III trial in previously untreated patients with acute myeloid leukaemia, who received daunorubicin, etoposide,

Conclusion

In this review we have combined well-documented histological knowledge about the blood–testis barrier with more recently published findings on the immunology and expression, function, and imaging of drug-efflux pumps. Histological data cannot fully explain all characteristics of the blood–testis barrier. Efflux pumps are complementary to the physicochemical properties of the barrier. In addition, the testes are protected from the immune system by the expression of Fas ligand on Sertoli cells

Search strategy and selection criteria

References were identified through searches of Medline and PubMed. The main search terms used were “testis”, “blood–testis barrier”, and “testicular tumour”. They were com bined with the following terms: “histology”, “immuno-histochemistry”, “electron microscopy”, “multi-drug resistance”, “efflux pump”, “P-glycoprotein”, “multidrug resistance protein 1”, “emission tomography”, and “immunology”. Further relevant reference papers were selected from the reference lists of the retrieved

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