Osteopontin: A Molecular Link Between Nicotine and Pancreatic Cancer
Chipitsyna et al., pp. 276–285
Study after study has confirmed that cigarette smoking is one of the biggest risk factors for developing pancreatic cancer but the molecular connections between the two are still largely unexplored. In this issue, Chipitsyna et al. present evidence that the nicotine in cigarettes increases the expression of osteopontin, a protein known to promote cancer cell survival, proliferation, invasion and metastasis.
Osteopontin, a secreted, integrin-binding protein, is found in a variety of body fluids. It was initially discovered as an inducible marker of transformation of epithelial cells and later was shown to be overexpressed in a variety of cancers, including lung, breast, cancer, stomach and pancreatic cancer. The latter prompted the authors to investigate whether osteopontin might play a role in smoking-induced pancreatic cancer.
In their experiments, osteopontin mRNA and protein levels went up in pancreatic cancer cell lines when treated with physiologically relevant nicotine levels. Similarly, rats exposed to cigarette smoke showed a dose-dependent increase in pancreatic osteopontin levels that paralleled the rise in pancreatic and plasma nicotine levels. When the researchers compared endogenous levels of osteopontin in human patients they found that the average osteopontin levels in pancreatic ductal adenocarcinoma (PDA) cells were significantly higher than those in nonmalignant or premalignant lesions. Interestingly, only 27% of patients with premalignant lesions were smokers, whereas 64% of malignant lesions came from patients who were smokers, supporting the hypothesis that nicotine may contribute to PDA pathogenesis through upregulation of osteopontin.
HPV-Positive Tonsillar Cancer on the Rise
Näsman et al., pp. 362–366
Tonsillar squamous cell carcinoma (SSC) is the most common oropharyngeal cancer in Sweden. In an earlier study, the authors reported that the incidence of tonsillar cancer as well as the proportion of HPV-positive tonsillar cancer tripled in the county of Stockholm between 1970 and 2002, despite a decline in smoking and smoking-related cancers during the same period. In their latest study, they found that the trend continued unabated during the last decade. Now, almost all patients diagnosed with tonsillar SCC in this area have HPV-positive tumors (93%).
To follow up on their initial findings, Näsman et al. obtained 98 pretreatment samples from patients diagnosed with tonsillar SCC between 2003–2007 and tested them for the presence of HPV DNA as well as HPV-16 E6 and E7 RNA. They found HPV DNA in 83 of 98 tonsillar SCC biopsies and 77 of those were HPV-16 positive. In summary, the incidence rate of HPV-positive tumors almost doubled each decade between 1970 and 2007, in parallel with a decline in HPV-negative tumors.
The fact that HPV-16 E6 and E7—both known to be necessary for carcinogenesis in cervical carcinoma—were expressed in the majority of the analyzed tumors suggests that HPV-16 plays an important role in the etiology of tonsillar carcinoma. On the upside, the availability of vaccines against HPV types 16 and 18 raises the possibility that vaccination may be able to put a stop to ever-increasing rates of HPV-positive tonsillar cancer.
Pulsed Electric Field Therapy to Zap Melanoma
Nuccitelli et al., pp. 438–445
Using electric fields to bust cancer cells is not a new idea. Electrochemotherapy combines conventional chemotherapy with a short high-voltage pulsed electric field to render the membrane of the tumor cells more porous, allowing toxic drugs to slip inside the cells. Hyperthermia therapy uses electric fields, typically in the radio frequency band, to kill tumors by heating them to temperatures above 42°C. Others employ 100-μs pulses of 2.5 kV/cm amplitude to irreversibly permeabilize cells, leading to necrosis. Nuccitelli et al. discovered that ultrashort electrical pulses can be used as a purely electrical cancer therapy that kills tumors without hyperthermia or drugs.
When the researchers applied 300 high-voltage (40 kV/cm), ultrashort (300 ns) electrical pulses to murine melanomas in vivo the treatment triggered both necrosis and apoptosis, resulting in complete remission on an average of 47 days. None of the 17 melanomas treated with nanosecond pulsed electric fields (nsPEFs) recurred during a 4-month period after the initial melanoma had disappeared. The pulses reduced the blood flow to the tumor and increased intracellular Ca2+ , both of which are important signals for initiating programmed cell death.
Researchers at the University of Southern California have successfully treated a single patient suffering from basal cell carcinoma with nsPEFs. The patient went into complete remission after only one treatment, suggesting that nsPEF, which has proven very effective for mouse melanoma, might be equally as effective for the treatment of human melanoma.