Head and Neck Cancer Studies Suggest Alternative Markers More Prognostically Useful than HPV DNA Testing
Reporter: Aviva Lev-Ari, PhD, RN
NEW YORK (GenomeWeb News) – The presence or absence of human papillomavirus DNA on its own in an individual’s head or neck cancer does not provide enough information to help predict a patient’s survival, according to a pair of new papers in the journal Cancer Research.
Two research teams — headed by investigators at Brown University and Heidelberg University, respectively — looked at the reliability of using PCR-based HPV testing to determine which head and neck squamous cell carcinomas were HPV-related and, thus, more apt to respond to treatment.
Previous studies have shown that individuals with HPV-associated head and neck cancers tend to have more favorable outcomes than individuals whose head and neck cancers that are not related to HPV infection.
“Everybody who has studied it has shown that people with virally associated disease do better,” Brown University pathology researcher Karl Kelsey, a senior author on one of the new studies, explained in a statement.
“There are now clinical trials underway to determine if they should be treated differently,” he added. “The problem is that you need to appropriately diagnose virally related disease, and our data suggests that people need to take a close look at that.”
For their part, Kelsey and his co-authors from the US and Germany assessed the utility of testing for the presence of HPV by various means in individuals with head and neck cancer. This included PCR-based tests for HPV DNA in the tumor itself, tests aimed at detecting infection-associated antibodies in an individual’s blood, and tests for elevated levels of an HPV-related tumor suppressor protein.
For 488 individuals with HNSCC, researchers did blood-based testing for antibodies targeting HPV16 in general, as well as testing for antibodies that target the viral proteins E6 and E7.
For a subset of patients, the team assessed the tumors themselves for the presence of HPV DNA and/or for elevated levels of the host tumor suppressor protein p16.
Based on patterns in the samples, the group determined that the presence of viral E6 and E7 proteins in the blood was linked to increased survival for individuals with an oropharyngeal form of HNSCC, which affects part of the throat known as the oropharynx.
A positive test for HPV DNA alone was not significantly linked to head and neck cancer outcomes. On the other hand, when found in combination with E6 and E7 expression, a positive HPV16 test did coincide with improved oropharyngeal cancer outcomes.
Likewise, elevated levels of p16 in a tumor were not especially informative on their own, though they did correspond to better oropharyngeal cancer survival when found together with positive blood tests for E6 and E7.
Based on these findings, Kelsey and his team concluded that “[a] stronger association of HPV presence with prognosis (assessed by all-cause survival) is observed when ‘HPV-associated’ HNSCC is defined using tumor status (HPV DNA or P16) and HPV E6/E7 serology in combination rather [than] using tumor HPV status alone.”
In a second study, meanwhile, a German group that focused on the oropharyngeal form of the disease found its own evidence arguing against the use of HPV DNA as a solo marker for HPV-associated head and neck cancer.
For that analysis, researchers assessed 199 fresh-frozen oropharyngeal squamous cell carcinoma samples, testing the tumors for HPV DNA and p16. They also considered the viral load in the tumors and looked for gene expression profiles resembling those described in cervical carcinoma — another cancer associated with HPV infection.
Again, the presence of HPV DNA appeared to be a poor indicator of HPV-associated cancers or predictor of cancer outcomes. Whereas nearly half of the tumors tested positive for HPV16 DNA, just 16 percent and 20 percent had high viral loads and cervical cancer-like expression profiles, respectively.
The researchers found that a subset of HPV DNA-positive tumors with high viral load or HPV-associated expression patterns belonged to individuals with better outcomes. In particular, they found that cervical cancer-like expression profiles in oropharyngeal tumors coincided with the most favorable outcomes, while high viral load in the tumors came a close second.
“We showed that high viral load and a cancer-specific pattern of viral gene expression are most suited to identify patients with HPV-driven tumors among patients with oropharyngeal cancer,” Dana Holzinger, that study’s corresponding author, said in a statement.
“Once standardized assays for these markers, applicable in routine clinical laboratories, are established, they will allow precise identification of patients with oropharyngeal cancer with or without HPV-driven cancers and, thus, will influence prognosis and potentially treatment decisions,” added Holzinger, who is affiliated with the German Cancer Research Center and Heidelberg University.
In a commentary article online today in Cancer Research, Eduardo Méndez, a head and neck surgery specialist with the University of Washington and Fred Hutchinson Cancer Research Center, discussed the significance of the two studies and their potential impact on oropharyngeal squamous cell carcinoma prognoses and treatment.
But he also cautioned that more research is needed to understand whether the patterns described in the new studies hold in other populations and to tease apart the prognostic importance of HPV infection in relation to additional prognostic markers.
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SOURCE
PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.