Desmoplasia: a response or a niche?

Summary: Desmoplasia-the presence of a rich stroma around a tumor-has long been associated with a poor clinical outcome in patients with cancer. It is considered to be a response to the presence of invasive tumor cells. There is now evidence that desmoplasia is the result of coordinated changes in several stromal cells under the control of a single gene product, CD36, whose repression leads to a decrease in fat accumulation and an increase in matrix deposition. The presence of these changes in tumor-free human breast tissue strongly suggests that desmoplasia may precede and not always follow the presence of malignant cells. This concept has an important clinical implication for women at high risk of developing breast carcinoma, considering that the presence of desmoplasia in normal breast tissue detected in the form of mammographic density is one of the strongest risk factors. Cancer Discov; 2(9); 772-4. ?2012 AACR.     

Pharmacogenomics: a reality or still a promise?

Although notable progress has been made in the treatment of non-small-cell lung cancer (NSCLC) in recent years, this disease is still associated with a poor prognosis for most patients. Modern techniques have facilitated the identification of specific genetic factors that may play a role in disease progression and patient response to therapy, prompting research efforts to identify the clinical predictors of outcome for NSCLC. Recent evidence suggests that the application of a pharmacogenomic approach has the potential to greatly improve survival in certain subpopulations of patients with NSCLC, which could profoundly influence the decision-making process used in evolving treatment strategies for this malignancy.     

TNF: a tumor-suppressing factor or a tumor-promoting factor?

TNF-α is a major inflammatory cytokine named for its ability to induce rapid hemorrhagic necrosis of experimental cancers. During efforts to harness this antitumor activity in cancer treatments in the 1980s, a paradoxical tumor-promoting role of TNF became apparent. The cellular and molecular complexity of mammalian tumor microenvironments makes these opposing effects difficult to study. The fruit fly Drosophila melanogaster provides a simpler model system for studying complex cellular and genetic interactions that lead to tumor formation and progression. The paper from Marcos Vidal's group shows that both the tumor-suppressing and tumor-promoting roles of TNF are conserved in Drosophila, and that oncogenic Ras is the switch. The links between inflammation and cancer are now more fully understood, but it is still not clear whether TNF has potential as a target or a therapeutic in malignant disease, or both. Research in an invertebrate organism may provide important insights.     

Cancer cachexia: a nutritional or a systemic inflammatory syndrome?

Cancer cachexia has long been perceived as a nutritional syndrome. However, nutritional interventions have continued to be ineffective. With the recent recognition of the importance of systemic inflammation in the definition of this syndrome and treatment, has the time come to consider whether this syndrome is primarily a manifestation of systemic inflammation with the consequent implications for future treatment?Subject terms: Cancer metabolism, Cancer metabolism     

Resistance to trastuzumab: a necessary evil or a temporary challenge?

The aim of this review article is to examine the potential mechanisms of resistance to trastuzumab. In the clinical setting, when trastuzumab is given as a single agent for first-line treatment of HER2-overexpressing metastatic breast cancer, it is associated with a 40% objective response rate. In the remaining cases, no tumor regression is observed, although HER2 protein is overexpressed and/or the corresponding gene is amplified. Hence, some other factors besides HER2 must play a role in determining the level of sensitivity to trastuzumab. The identification of the potential mechanisms of resistance to trastuzumab can be very helpful for the development of new compounds, which might overcome that resistance and/or have additive/synergistic antitumor effect when given in association with trastuzumab. Moreover, thorough understanding of the HER2 pathway is essential to the identification of new predictive markers of response to trastuzumab that will help to better define the patients who are most likely to benefit from this drug.     

Mammary cancer and epithelial stem cells: a problem or a solution?

The existing paradigms for stem cells in adult tissues include the integument, the alimentary canal, the lung, the liver, skeletal muscle and bone marrow. The mammary gland, by contrast, is the 'new kid on the block'. What little is known about stem cells in the mammary gland indicates that they possess a prodigious capacity for self-renewal. More importantly, in rodents, they persist with undiminished reproductive vigor throughout the organism's lifetime without regard to age or reproductive history. Do these stem cells represent primary targets for mammary neoplasia? If so, what are the implications for prevention/therapy?     

Ameloblastic fibrosarcoma or odontogenic carcinosarcoma: a matter of classification?

A biphasic odontogenic tumor with aggressive clinical behaviour is reported. The tumor arose posterior to the right mandibular third molar involving the angle of the mandible and the ascending ramus. Within a 5 years period the patient suffered from two episodes of local progression and final disease generalization occurred 6 years after initial surgical therapy. On histopathologic evaluation, both recurrences and the distant metastasis preserved the biphasic pattern seen in the primary tumor with both epithelial and mesenchymal components exhibiting clear cytological features of malignancy. There was no evidence of sarcomatous overgrowth within the progression of the tumor. By contrast, the proportion of the epithelial component was even enlarged in the second recurrence. Thus, both pathologic features and clinical behaviour clearly distinguishes this tumor from ameloblastic fibrosarcoma and demonstrates the clear morphological as well as clinical characteristics of a true malignant mixed type tumor with a definite sarcomatous and carcinomatous component. Thus, even though a very rare lesion, our case supports the consideration of the odontogenic carcinosarcoma as an individual entity.     

MicroRNA function in cancer: oncogene or a tumor suppressor?

MicroRNAs (miRNAs) are small noncoding, double-stranded RNA molecules that can mediate the expression of target genes with complementary sequences. About 5,300 human genes have been implicated as targets for miRNAs, making them one of the most abundant classes of regulatory genes in humans. MiRNAs recognize their target mRNAs based on sequence complementarity and act on them to cause the inhibition of protein translation by degradation of mRNA. Besides contributing to development and normal function, microRNAs have functions in various human diseases. Given the importance of miRNAs in regulating cellular differentiation and proliferation, it is not surprising that their misregulation is linked to cancer. In cancer, miRNAs function as regulatory molecules, acting as oncogenes or tumor suppressors. Amplification or overexpression of miRNAs can down-regulate tumor suppressors or other genes involved in cell differentiation, thereby contributing to tumor formation by stimulating proliferation, angiogenesis, and invasion; i.e., they act as oncogenes. Similarly, miRNAs can down-regulate different proteins with oncogenic activity; i.e., they act as tumor suppressors. This review will highlight the recent discoveries regarding miRNAs and their importance in cancer.     

DPPIV/CD26: a tumor suppressor or a marker of malignancy?

Dipeptidyl peptidase IV (DPPIV/CD26) is a multifunctional protein with intrinsic peptidase activity that inactivates or degrades some bioactive peptides. It is the main cellular binding protein for ecto-adenosine deaminase and interacts with extracellular matrix proteins, besides participating in different signaling pathways. Due to these multiple functions, DPPIV/CD26 has been shown to be closely related to the tumor process. It has been reported that the progression of certain types of cancer is accompanied by a decrease in DPPIV/CD26 expression, and studies have shown that the malignant phenotype can be reverted when DPPIV/CD26 expression is induced in these cancer cells, characterizing this protein as a tumor suppressor. On the other hand, DPPIV/CD26 was described as a protein associated with invasion and metastatic spread, characterizing it as a marker of malignancy. Thus, this review explores the roles of DPPIV/CD26 expression in tumor progression in different types of cancer and demonstrates the importance of this protein as a promising therapeutic target and tumor biomarker.     

What Causes Waldenström's Macroglobulinemia: Genetic or Immune-Related Factors,or a Combination?

Population-based studies suggest a role for chronic immune stimulation and genetic factors in the causation of lymphoplasmacytic lymphoma (LPL)/Waldenström's macroglobulinemia (WM). In this review we summarize and discuss our current understanding on etiology and pathogenesis of LPL/WM. We also highlight on gaps in the literature and propose future directions for population-based and molecular studies designed to expand our knowledge and uncover biological underpinnings of identified associations. Further, we address clinical implications and provide perspective on the relevance of these data for patient counseling and clinical follow-up.