No abstract

In this review, we highlight recent discoveries regarding mechanisms contributing to nerve-cancer crosstalk and the effects of nerve-cancer crosstalk on tumor progression and dissemination. High intratumoral nerve density correlates with poor prognosis and high recurrence across multiple solid tumor types. Recent research has shown that cancer cells express neurotrophic markers such as nerve growth factor, brain-derived neurotrophic factor, and glial cell-derived neurotrophic factor and release axon guidance molecules such as Ephrin B1 to promote axonogenesis. Tumor cells recruit new neural progenitors to the tumor milieu and facilitate their maturation into adrenergic infiltrating nerves. Tumors also rewire established nerves to adrenergic phenotypes via exosomeinduced neural reprogramming by p53-deficient tumors. In turn, infiltrating sympathetic nerves facilitate cancer progression. Intratumoral adrenergic nerves release noradrenaline to stimulate angiogenesis via vascular endothelial growth factor signaling and enhance the rate of tumor growth. Intratumoral parasympathetic nerves may have a dichotomous role in cancer progression and may induce Wnt-β-catenin signals that expand cancer stem cells. Importantly, infiltrating nerves not only influence the tumor cells themselves but also impact other cells of the tumor stroma. This leads to enhanced sympathetic signaling and glucocorticoid production, which influences neutrophil and macrophage differentiation, lymphocyte phenotype, and potentially lymphocyte function. Although much remains unexplored within this field, fundamental discoveries underscore the importance of nerve-cancer crosstalk to tumor progression and may provide the foundation for developing effective targets for the inhibition of tumor-induced neurogenesis and tumor progression.

Recurrent, metastatic disease represents the most frequent cause of death for patients with thyroid cancer, and radioactive iodine (RAI) remains a mainstay of therapy for these patients. Unfortunately, many thyroid cancer patients have tumors that no longer trap iodine, and hence are refractory to RAI, heralding a poor prognosis. RAI-refractory (RAI-R) cancer cells result from the loss of thyroid differentiation features, such as iodide uptake and organification. This loss of differentiation features correlates with the degree of mitogen-activated protein kinase (MAPK) activation, which is higher in tumors with BRAF (B-Raf proto-oncogene) mutations than in those with RTK (receptor tyrosine kinase) or RAS (rat sarcoma) mutations. Hence, inhibition of the mitogen-activated protein kinase kinase-1 and -2 (MEK-1 and -2) downstream of RAF (rapidly accelerated fibrosarcoma) could sensitize RAI refractivity in thyroid cancer. However, a significant hurdle is the development of secondary tumor resistance (escape mechanisms) to these drugs through upregulation of tyrosine kinase receptors or another alternative signaling pathway. The sodium iodide symporter (NIS) is a plasma membrane glycoprotein, a member of solute carrier family 5A (SLC5A5), located on the basolateral surfaces of the thyroid follicular epithelial cells, which mediates active iodide transport into thyroid follicular cells. The mechanisms responsible for NIS loss of function in RAI-R thyroid cancer remains unclear. In a study of patients with recurrent thyroid cancer, expression levels of specific ribosomal machinery—namely PIGU (phosphatidylinositol glycan anchor biosynthesis class U), a subunit of the GPI (glycosylphosphatidylinositol transamidase complex—correlated with RAI avidity in radioiodine scanning, NIS levels, and biochemical response to RAI treatment. Here, we review the proposed mechanisms for RAI refractivity and the management of RAI-refractive metastatic, recurrent thyroid cancer. We also describe novel targeted systemic agents that are in use or under investigation for RAI-refractory disease, their mechanisms of action, and their adverse events.

Although immunotherapy has achieved impressive durable clinical responses, many cancers respond only temporarily or not at all to immunotherapy. To find novel, targetable mechanisms of resistance to immunotherapy, patient-derived melanoma cell lines were transduced with 576 open reading frames, or exposed to arrayed libraries of 850 bioactive compounds, prior to co-culture with autologous tumor-infiltrating lymphocytes (TILs). The synergy between the targets and TILs to induce apoptosis, and the mechanisms of inhibiting resistance to TILs were interrogated. Gene expression analyses were performed on tumor samples from patients undergoing immunotherapy for metastatic melanoma. Finally, the effect of inhibiting the top targets on the efficacy of immunotherapy was investigated in multiple preclinical models. Aurora kinase was identified as a mediator of melanoma cell resistance to T-cell-mediated cytotoxicity in both complementary screens. Aurora kinase inhibitors were validated to synergize with T-cell-mediated cytotoxicity in vitro. The Aurora kinase inhibition-mediated sensitivity to T-cell cytotoxicity was shown to be partially driven by p21-mediated induction of cellular senescence. The expression levels of Aurora kinase and related proteins were inversely correlated with immune infiltration, response to immunotherapy and survival in melanoma patients. Aurora kinase inhibition showed variable responses in combination with immunotherapy in vivo, suggesting its activity is modified by other factors in the tumor microenvironment. These data suggest that Aurora kinase inhibition enhances T-cell cytotoxicity in vitro and can potentiate antitumor immunity in vivo in some but not all settings. Further studies are required to determine the mechanism of primary resistance to this therapeutic intervention.

No abstract

BACKGROUND:The survival benefit of elective neck dissection (END) for patients with cutaneous squamous cell carcinoma (cSCC) of the head and neck and no evidence of regional metastasis (cN0) has never been reported. The aim of this study was to determine the effect of END on patient survival. METHODS: The authors included patients with head and neck cSCC who had undergone primary surgery from 1995 to 2017. The primary end point was survival, and the secondary end points were the incidence of occult regional disease and regional disease control. To assess the impact of END on survival, the authors used multivariable Cox proportional hazards models with propensity score and matching techniques for internal validation. RESULTS: A total of 1111 patients presented with no evidence of nodal disease; 173 had END, and 938 were observed. Adjuvant radiotherapy to the neck was administered to 101 patients (9%). END resulted in a 5-year overall survival rate of 52%, whereas the rate was 63% in the observation group (P = .003 [log-rank]). The 5-year disease-free survival rate for patients undergoing END was similar to that for the observation group (73% vs 75%; P = .429). A multivariate regression model showed that the performance of END was not associated with improved rates of overall, disease-specific, or disease-free survival; similarly, among patients with advanced disease (T3-4), those who underwent END did not have improved survival rates. CONCLUSIONS: Among patients with cSCC of the head and neck, observation of the neck nodes resulted in noninferior survival rates in comparison with END at the time of primary surgery. Further studies are required to elucidate the role of END in patients with advanced disease. Cancer 2021;127:4413-4420.

Hoxa9 is expressed in hematopoietic stem and progenitor cells although this expression is usually diminished as these cells undergo differentiation. In addition, aberrant expression of Hoxa9 is strongly associated with both T-cell and myeloid leukemia in mice and humans. Despite this strong association, enforced expression of Hoxa9 in murine bone marrow or thymus has only shown a modest ability to transform cells. To investigate this question, we used Vav regulatory elements to generate a transgenic mouse that targets Hoxa9 overexpression to all hematopoietic tissues. High level expression of the Hoxa9 transgene in the hematopoietic compartment was associated with embryonic lethality, as no pups from founders that expressed high levels of the transgene were born live. However, offspring of an additional founder line, which expressed lower levels of Hoxa9, developed a precursor T cell lymphoblastic leukemia/lymphoma (pre-T LBL), accompanied by spontaneous Notch1 mutations. In contrast to most murine models of leukemia associated with Hoxa9 overexpression, the Vav-Hoxa9 mice did not overexpress other Hoxa cluster genes, mir196b (a microRNA which is embedded in the Hoxa locus), Meis1, or Pbx3. The Hoxa9 transgenic mouse reported here provides a suitable system for the study of Hoxa9 collaborators that drive myeloid and lymphoid malignant transformation.

Background: Many cancer patients seek traditional Chinese medicine (TCM), the prevalence varying with diagnosis, comorbidities, and demographics. Interventions sought include acupuncture, massage, herbs, diet, and exercise, usually combined with conventional therapies. It is not known what proportion of TCM practitioners care for cancer patients, their cancer specific training or caseload, what interventions they employ, their outcomes, and their communication patterns with conventional oncologists. Methods: A survey was mailed to all 2213 licensed acupuncturists in the 9-county San Francisco Bay Area gathering descriptive statistics. Results: A total of 472 (21%) responded by mail or web-based Research Electronic Data Capture (REDCap) tool. Most respondents (77%) reported caring for patients with cancer, with 29% reporting having 6 to 10 years of practice experience, and 44.2% having 0 to 20 hours of training specific to the needs of patients with cancer. Improving quality of life was reported by 94% as what their treatment offered cancer patients as well as the area where treatment was felt to have the greatest impact. The most useful TCM modalities were acupuncture (98%), herbs (79%), diet (72%), moxibustion (46%), and meditation instruction (44%). Absence of adverse reactions was noted by 95%. Ninety-one percent reported “never” or “hardly ever” having been contacted by patients’ oncologists to discuss treatment. Conclusions: Many acupuncturists seeing cancer patients have significant clinical experience and have sought specialized training. Improved communication is needed between TCM practitioners and oncologists sharing care of cancer patients.