Stem Cell Theory of Cancer: Origin of Tumor Heterogeneity and Plasticity

In many respects, heterogeneity is one of the most striking revelations and common manifestations of a stem cell origin of cancer. We observe heterogeneity in myriad mixed tumors including testicular, lung, and breast cancers. We recognize heterogeneity in diverse tumor subtypes in prostate and kidney cancers. From this perspective, we illustrate that one of the main stem-ness characteristics, i.e., the ability to differentiate into diverse and multiple lineages, is central to tumor heterogeneity. We postulate that cancer subtypes can be meaningless and useless without a proper theory about cancer’s stem cell versus genetic origin and nature. We propose a unified theory of cancer in which the same genetic abnormalities, epigenetic defects, and microenvironmental aberrations cause different effects and lead to different outcomes in a progenitor stem cell versus a mature progeny cell. We need to recognize that an all-encompassing genetic theory of cancer may be incomplete and obsolete. A stem cell theory of cancer provides greater universality, interconnectivity, and utility. Although genetic defects are pivotal, cellular context is paramount. When it concerns tumor heterogeneity, perhaps we need to revisit the conventional wisdom of precision medicine and revise our current practice of targeted therapy in cancer care.

The Clinical and Pathological Characteristics of Mammary Neoplasms with Malignant Mesenchymal Components in Female Dogs

Mammary neoplasms with malignant mesenchymal components are not common in female dogs, and they are poorly understood. As such, this study aimed to describe the clinical presentation, histological findings, and the COX-2 immunohistochemical expression of mammary neoplasms in female dogs with malignant mesenchymal components, as well as verify the relationships between the different neoplasm types and these aspects. We selected 41 female mammary neoplasms (23 carcinosarcomas, 16 sarcomas, and 2 sarcomas in mixed tumors). Medical records were reviewed to obtain clinical data. Subsequently, histological slides were analysed to establish histological parameters, and immunohistochemistry was used to assess the expression of COX-2 receptors. Carcinosarcomas and sarcomas developed as large tumours, mainly in the abdominal and inguinal mammary glands, with frequent intratumoral necrosis and a low frequency of nodal metastasis. Fifty-eight percent of the cases of malignant mesenchymal proliferation were identified as osteosarcomatous, and 24.5% chondrosarcomatous and fibrosarcomastous each. The osteosarcomatous pattern was the most predominant type in sarcomas and carcinosarcomas, and was the only one that resulted in vascular invasion, regional lymph node metastases, and higher histologic grades. High COX-2 expression was detected in 10% of the carcinosarcomas and 25% of the sarcomas. In conclusion, sarcomas and carcinosarcomas showed similar results regarding the clinical and pathological aspects. Discovering carcinosarcomas and sarcomas with high COX-2 expression suggests that, in some cases, these neoplasms may respond to therapy with COX-2 inhibitors.

Sub-centimeter lymphadenopathy in germ cell testicular cancer: An ongoing surveillance challenge.

e17011 Background: Correct identification of retroperitoneal disease is essential for proper staging and management in germ cell tumors. A size threshold of a 10mm diameter has high specificity in assessing nodal metastases, but sensitivity can be poor at this level and many patients have sub-centimeter lymphadenopathy on post-orchidectomy staging. As many staging scans are done soon after surgery, these may represent reactive lymph nodes. We aimed to assess the prevalence of sub-centimeter lymphadenopathy on baseline imaging in our patients, and its association with recurrence. Methods: Records of patients diagnosed with testicular germ cell cancer in a tertiary cancer center (n = 55, 2015-2020) were reviewed (median followup of 26 months, range 1-59). Lymphadenopathy size measurements were taken from the scan report, which had been authorized by a radiology consultant. Results: Patients had a median age of 34 (range 19-63). 37 (67%) had pure seminomas, 2 (4%) pure embryonal tumors, 12 (22%) mixed tumors with a primarily (> 50%) embryonal component, and 4 (7%) other mixed types. 48 (87%) had stage 1 disease, 3 (6%) stage 2 and 4 (7%) stage 3 disease. 26 (47%) had CT staging preoperatively, of the remainder 69% (n = 20) were staged in the first 48 postoperative hours. 28 (51%) had no lymphadenopathy, 15 (27%) had sub-centimeter lymphadenopathy within the landing zone, 8 (15%) had lymphadenopathy measuring > 1 cm within the landing zone, 4 (7%) had lymphadenopathy elsewhere. 7 had immediate chemotherapy, 48 entered surveillance. For the 14 with sub-centimeter lymphadenopathy within the landing zone who did not have immediate chemotherapy, 3 regressed, 8 were stable. 2 underwent a PET for further assessment, 1 a biopsy. 3 increased in size. 6 patients on surveillance had a recurrence – of these 2 had seminomas with no baseline lymphadenopathy, 4 had mixed primarily embryonal tumors (3 with sub-centimeter lymphadenopathy (0.6, 0.7 and 0.9 cm each), one with a 1.3cm para-aortic lymph node). Of those 4, only 1 had significantly elevated HCG pre-operatively, all recurred in the sites of previously noted lymphadenopathy. Those with mixed, primarily embryonal disease with lymphadenopathy (representing 50% of such patients on surveillance) had a higher recurrence risk than other patients on surveillance (OR: 153, 95% CI 6-3709, p= 0.002) Those undergoing preoperative/delayed postoperative imaging (n = 28) were equally likely to have lymphadenopathy to those having imaging in the first 7 postoperative days ( X2 (3, N= 27) = 2.9, p= 0.4). 1 patient had died (unrelated causes), all others were disease-free at most recent followup. Conclusions: Sub-centimeter lymphadenopathy is more likely to be benign in those with seminomas, but even small volume lymphadenopathy in those with mixed tumors with a primarily embryonal component may represent metastatic disease, and should be monitored closely.

A Unique Case of Corticomedullary Mixed Tumor Composed of Both Adrenal Cortical Cells and Pheochromocytes

Introduction or Background: Corticomedullary mixed tumors of the adrenal gland was first described in 1969 by Mathison and Waterhouse. It is defined as a single tumor mass of the adrenal gland that histopathologically has presence of adrenal cortical and medullary cells. Such mixed tumors involving the cortical and medullary components of the adrenal glands are very rare. Clinical Case (including diagnostic evaluation, treatment, and follow-up):A 67 year old woman with a history of hypertension and osteoporosis presents for incidental adrenal adenoma. Hypertension was controlled well with olmesartan 40mg, hctz 25mg, and amlodipine 2.5mg. Abdominal CT scan showed a 2.6 cm enhancing left adrenal nodule with delayed wash- out phase. Biochemical testing showed elevated plasma free metanephrine (132pq/ml, n < or = 57pq/ml) and abnormal 1mg dexamethasone suppression test (10.4mcg/dL, n <2mcg/dL). ACTH was suppressed. Patient underwent left adrenalectomy, after pretreatment with doxazosin. Surgical pathology report showed an unusual neoplasm consisting of a single nodule composed of intermixed aggregates of cortical cells and pheochromocytes displaying morphologic features of adrenal adenoma and pheochromocytoma. Also intermixed with the adenoma was a 3mm myelolipoma. Post surgery, the patient was treated with hydrocortisone for symptoms of adrenal insufficiency. Post surgery, she was able to stop amlodipine and hctz and is on 10 mg olmesartan on alternate days.. She remains on a weaning dose of hydrocortisone at the time of abstract submission. Clinical Lesson(s) or Conclusion(s) (emphasizing the learning point[s] and implications for clinical practice)This unique case report highlights the importance of appropriate workup for incidental adrenal adenoma and keeping in mind the rare possibility of mixed endocrine tumours. A single mixed tumor of the adrenal gland is rare but exhibits distinct morphologic features of both a cortisol producing tumor along with a pheochromocytoma. Furthermore, a concurrent intermixing of a myelolipoma within an adrenal corticomedullary mixed tumor is rarely reported.

TERT promoter mutation and chromosome 6 loss define a high-risk subtype of ependymoma evolving from posterior fossa subependymoma

Subependymomas are benign tumors characteristically encountered in the posterior fossa of adults that show distinct epigenetic profiles assigned to the molecular group “subependymoma, posterior fossa” (PFSE) of the recently established DNA methylation-based classification of central nervous system tumors. In contrast, most posterior fossa ependymomas exhibit a more aggressive biological behavior and are allocated to the molecular subgroups PFA or PFB. A subset of ependymomas shows epigenetic similarities with subependymomas, but the precise biology of these tumors and their potential relationships remain unknown. We therefore set out to characterize epigenetic traits, mutational profiles, and clinical outcomes of 50 posterior fossa ependymal tumors of the PFSE group. On histo-morphology, these tumors comprised 12 ependymomas, 14 subependymomas and 24 tumors with mixed ependymoma–subependymoma morphology. Mixed ependymoma–subependymoma tumors varied in their extent of ependymoma differentiation (2–95%) but consistently exhibited global epigenetic profiles of the PFSE group. Selective methylome analysis of microdissected tumor components revealed CpG signatures in mixed tumors that coalesce with their pure counterparts. Loss of chr6 (20/50 cases), as well as TERT mutations (21/50 cases), were frequent events enriched in tumors with pure ependymoma morphology (p < 0.001) and confined to areas with ependymoma differentiation in mixed tumors. Clinically, pure ependymoma phenotype, chr6 loss, and TERT mutations were associated with shorter progression-free survival (each p < 0.001). In conclusion, our results suggest that subependymomas may acquire genetic and epigenetic changes throughout tumor evolution giving rise to subclones with ependymoma morphology (resulting in mixed tumors) that eventually overpopulate the subependymoma component (pure PFSE ependymomas).

Limited efficacy of lenvatinib in heavily pretreated anaplastic thyroid cancer: a French overview

Anaplastic thyroid cancer (ATC) is a rare lethal disease. Lenvatinib is an off-label therapeutic option for ATC in most countries, except in Japan. The aim of this multicenter retrospective survey was to analyze the efficacy and the toxicity profile of off-label lenvatinib treatment in all adults advanced ATC patients, in France. Of the 23 patients analysed (14 males; mean age 64 years), 15 were pure ATC and 8 were mixed tumors (i.e. with a differentiated or poorly differentiated component). Prior treatments included neck external beam irradiation in 74%, at least one line of chemotherapy in 22 cases, two lines of chemotherapy in 11 patients, other TKI in 4 cases. A central RECIST assessment was performed. Since lenvatinib initiation, median PFS was 2.7 months (95% CI; 1.9–3.5) and median OS was 3.1 months (95% CI; 0.6–5.5). OS was significantly longer in case of mixed tumors compared with pure ATC (6.3 vs 2.7 months, P = 0.026). Best tumor response was partial response in two cases and stable disease in seven. Clinical improvement was achieved in seven patients. Lethal adverse events occurred in three patients, consisting in haemoptysis in two cases and pneumothorax in one case. Among long-surviving ATC patients (>6 months), four underwent biopsy of distant metastasis, revealing poorly differentiated histology; three of them had initial mixed ATC histology. Efficacy of lenvatinib appears limited, although pure vs mixed ATC disclose differences in disease aggressiveness and treatment response. Long-surviving ATC patients might benefit from biopsy of persistent disease, searching for histological transition or molecular target.

232 The epithelial-to-mesenchymal transition (EMT) contributes to immunosuppression in breast carcinomas and regulates their response to immune checkpoint blockade

BackgroundImmune checkpoint blockade (ICB) has generated some dramatic responses in certain types of human tumors, most notably, melanomas. However, the response of breast tumors has been largely limited. We have previously demonstrated that the residence of breast cancer cells in the epithelial or mesenchymal phenotypic states can itself be used as an important determinant of the success or failure of ICB. Specifically, we have shown that while epithelial tumors are sensitive to anti-CTLA4, mesenchymal tumors are highly resistant. Most strikingly, in tumors arising from a mixture of both cell types, a minority population (10%) of mesenchymal cells can cross-protect the vast majority (90%) of their epithelial neighbors from immune attack.1 However, the mechanisms underlying such cross-protection remain elusive. This is particularly important as most human breast cancers contain minority populations of such mesenchymal cells which can protect the tumor as a whole from immune attack.MethodsUsing a combination of transcriptomic and CRISPR/Cas9 approaches, we first identified that mesenchymal carcinoma cells express high levels of CD73, an ecto-enzyme that catalyzes the production of adenosine. Additionally, we used digital spatial profiling to determine whether CD73 expression differs across distinct epithelial and mesenchymal sectors in mixed tumors.ResultsAbrogation of CD73 from mesenchymal carcinoma cells prevented the assembly of an immunosuppressive tumor microenvironment and resulted instead in increased numbers of tumor-infiltrating lymphocytes and cross-presenting dendritic cells. Most strikingly, abrogation of CD73 sensitized previously refractory mesenchymal tumors completely to ICB. In the context of mixed tumors comprised of both epithelial and mesenchymal carcinoma cells, gradients in expression of CD73 were observed corresponding to the epithelial or mesenchymal sectors of these mixed tumors. Importantly, mixed tumors in which the minority population of mesenchymal carcinoma cells lacked the expression of CD73, were also sensitized partially to ICB. Thus, these mesenchymal carcinoma cells knocked out for CD73 could no longer protect their epithelial neighbors from immune attack.ConclusionsTaken together, our work suggests that mesenchymal carcinoma cells exert immune-suppressive effects which are also prominent in heterogeneous tumors. Furthermore, targeting the adenosinergic signaling pathway in mesenchymal carcinoma cells can potentiate the efficacy of ICB.ReferenceDongre A, Rashidian M, Reinhardt F, Bagnato A, Keckesova Z, Ploegh HL, Weinberg RA, Epithelial-to-mesenchymal transition contributes to immunosuppression in breast carcinomas. Cancer Res 2017 Aug 1;77(15):3982–3989.