Spotlight

Pap Smears Reduce the Incidence of Cervical Adenocarcinoma

Sasieni et al., pp. 525–529

It is widely assumed that Pap smear screening is not effective against adenocarcinoma because the concealed location of these cancers in the cervix makes them less amenable to detection at an early stage. Adenocarcinomas arise from the glandular lining of the endocervical canal and represent 15% of all cancers of the cervix. In contrast, squamous cell carcinomas develop from the outermost layer of the epithelium in the visible part of the cervix and progress through well-established premalignant lesions that can be detected by Pap smear screening. Consequently, incidence rates of squamous cell carcinoma have dropped by more than 80% in some countries of the developed world while numbers for adenocarcinoma remained the same or have even increased.

In a large, population-based, case-control study including more than 3000 British women with cervical cancer of any type, Sasieni and colleagues uncovered a small but significant impact of screening on the incidence of cervical adenocarcinoma. The protection offered by being screened within the last 10 years was low for adenocarcinoma (OR = 0.74) in comparison to squamous cell carcinoma (OR = 0.27). For the mixed type of the two cancers, adenosquamous carcinoma, screening offered similar protection as seen for squamous cell carcinoma alone (OR = 0.26). Incidence of adenocarcinoma was low within 2.5 years of a negative smear but could not be distinguished from background rates 4.5–5.5 years after negative testing.

The study offers hope that high-frequency screening combined with better smear taking and more careful cytology may improve detection of adenocarcinoma by Pap smear screening in the future.

TGF-β and Malignant Human Glioma: New Target for Therapy?

Tritschler et al., pp. 530–540

TGF-β plays fundamental roles in tissue homeostasis and in the malignant phenotype of glioblastoma. High TGF-β levels associated with this tumor may induce immunosuppression in the host, may promote tumor angiogenesis, invasion and/or metastasis and generally confer a poor prognosis to those affected with the disease.

Synthesis, release and activation of TGF-β are complex processes regulated at multiple levels. During its maturation, pro-TGF-β is proteolytically cleaved and remains noncovalently associated with an N-terminal peptide called the latency-associated peptide in an inactive complex termed the small latent complex (SLC). The SLC itself can become covalently attached to a protein called “latent TGF-β-binding protein” (LTBP) to form the large latent complex. It is thought that the four isoforms of LTBP may be involved in matrix protein binding of TGF-β and may thereby target the latent TGF-β complexes to specific storage sites and regulate their release into the extracellular space. Released TGF-β activates its receptor, leading to Smad2 and 3 phosphorylation and to specific changes in gene expression.

In this issue of IJC, Trischler and colleagues report that levels of LTBP-1 protein in vivo increase with the grade of malignancy in gliomas. Unexpectedly and despite its proposed inhibitory activity, overexpression of LTBP-1 in gliomas is associated with an increase in TGF-β activity. These observations identify LTBP-1 as an important modulator of TGF-β activity in glioma cells and as a possible contributor to the malignant phenotype of these tumors.

Rising Breast Cancer Risk in India

Gajalakshmi et al., pp. 662–665

India is the country with the largest estimated number of breast cancer deaths world-wide. In the past, incidence rates of breast cancer were traditionally low, especially in rural areas of the subcontinent, but have been steadily rising because of reproductive and lifestyle changes in urban regions. In the largest case-control study on breast cancer in India, Gajalakshmi and colleagues tie this rise in risk to a reduction in breastfeeding.

The study confirms a strongly decreased risk for breast cancer in premenopausal women with long lifetime duration of breastfeeding. An increased risk of breast cancer was linked with unmarried status, high educational level and high socioeconomic status in both pre- and postmenopausal women. Although long duration of breastfeeding was more common among women with low socioeconomic status, a protective effect was seen in premenopausal women of both low and high income status.

Why prolonged breastfeeding offers protection from breast cancer specifically in premenopausal women is presently unknown. A prolonged period of lactation has been associated with a longer period of lactational amenorrhea and reduced lifetime exposure to estrogens. Lactational amenorrhea is longer in India (11 months) than in Australian women (8.5 months) and is strongly influenced by the nutritional status of the mother. The authors advocate for better education of Indian women about the benefits associated with longer breastfeeding, not only related to the health of the child but also to that of the mother in order to help reduce the growing breast cancer burden in India.