Estrogen Activation of G-Protein–Coupled Estrogen Receptor 1 Regulates Phosphoinositide 3-Kinase and mTOR Signaling to Promote Liver Growth in Zebrafish and Proliferation of Human Hepatocytes

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Polyclonal breast cancer metastases arise from collective dissemination of keratin 14-expressing tumor cell clusters

Recent genomic studies challenge the conventional model that each metastasis must arise from a single tumor cell and instead reveal that metastases can be composed of multiple genetically distinct clones. These intriguing observations raise the question: How do polyclonal metastases emerge from the primary tumor? In this study, we used multicolor lineage tracing to demonstrate that polyclonal seeding by cell clusters is a frequent mechanism in a common mouse model of breast cancer, accounting for >90% of metastases. We directly observed multicolored tumor cell clusters across major stages of metastasis, including collective invasion, local dissemination, intravascular emboli, circulating tumor cell clusters, and micrometastases. Experimentally aggregating tumor cells into clusters induced a >15-fold increase in colony formation ex vivo and a >100-fold increase in metastasis formation in vivo. Intriguingly, locally disseminated clusters, circulating tumor cell clusters, and lung micrometastases frequently expressed the epithelial cytoskeletal protein, keratin 14 (K14). RNA-seq analysis revealed that K14⁺ cells were enriched for desmosome and hemidesmosome adhesion complex genes, and were depleted for MHC class II genes. Depletion of K14 expression abrogated distant metastases and disrupted expression of multiple metastasis effectors, including Tenascin C (Tnc), Jagged1 (Jag1), and Epiregulin (Ereg). Taken together, our findings reveal K14 as a key regulator of metastasis and establish the concept that K14⁺ epithelial tumor cell clusters disseminate collectively to colonize distant organs.During metastasis, cancer cells escape the primary tumor, travel through the circulation, and colonize distant organs. Conventional models of cancer progression propose that each metastasis arises from the clonal outgrowth of a single tumor cell and this conceptual framework is a foundation for models, such as epithelial-mesenchymal transition (EMT) and migratory cancer stem cells (1).Challenging the generality of the single-cell/single-metastasis model are long-standing clinical observations that tumor cell clusters (also termed “tumor clumps”) are also observed across the stages of metastasis. Tumor cell clusters are detected in the bloodstream of cancer patients (2), clusters can efficiently seed metastases (3), and though rare, circulating tumor cell (CTC) clusters have prognostic significance (4, 5). Furthermore, metastases are composed of multiple genetically distinct tumor cell clones, in mouse models of breast, pancreas, and small cell carcinoma (5–7), and in human metastatic prostate cancer patients (8). Taken together, these observations provide accumulating evidence that tumor cell clusters contribute to metastasis. However, they leave unresolved two important questions: how do tumor cell clusters emerge from the primary tumor, and which molecular features identify cell clusters that metastasize?An important clinical observation is that cancer cells invade the surrounding stroma as cohesive clusters in the majority of epithelial tumors, a process termed “collective invasion” (9, 10). In breast cancer, collective invasion is facilitated by invasive leader cells, a subpopulation of tumor cells that highly express keratin 14 (K14) and other basal epithelial markers (11). K14⁺ cells are migratory, protrusive, and lead trailing K14⁻ cells, while maintaining cell–cell cohesion and E-cadherin–based cell contacts.In this study, we sought to understand how these K14⁺ cells exit collective invasion strands in the primary tumor and travel to distant organs (12). One hypothesis is that collective invasion is an intermediate step toward eventual single-cell dissemination and monoclonal metastasis. However, tumor cell clusters are detected in circulation (5) and primary human breast tumors can disseminate collectively into the surrounding extracellular matrix in ex vivo assays (13–15). These data prompted an alternative hypothesis, that collectively invading K14⁺ cancer cells could initiate and complete the metastatic process as a cohesive multicellular unit. Here we define the clonal nature of metastases in a spontaneous mouse model of metastasis to the lungs (16, 17), in which the predominant invasive form in the primary tumor is collective invasion strands led by K14⁺ cells (11). We establish that the majority of metastases arise from polyclonal seeds, and show that disseminated tumor cell clusters are predominantly composed of K14⁺ cells. We propose a mechanism for polyclonal metastasis via the collective invasion, dissemination, and colonization of clusters of K14⁺ cancer cells.     

Unusual presentation of rectal adenocarcinoma

Metastatic tumors in the gastrointestinal tract are rare with an overall prevalence of 1-4 per cent in the postmortem series. Lung cancer, renal cell carcinoma, breast carcinoma and malignant melanoma are considered the most common primary tumors metastatic to the small bowel. Local duodenal metastasis from colonic cancer and cecum have been reported, but metastasis to the duodenum from rectosigmoid adenocarcinoma has not been reported before. We report the first case of metastasis in the duodenum from an adenocarcinoma of the rectum presented as a recurrent acute prerenal azotemia caused by volume depletion which had resulted from duodenal obstruction.     

The short- and long-term prognosis of patients with transmural and nontransmural myocardial infarctio

To compare the long-term prognosis in patients surviving transmural with patients surviving nontransmural myocardial infarctions, the records of 188 consecutive patients with clinical histories and enzyme elevations consistent with acute infarction were reviewed. According to standard electrocardiographic criteria the patients were divided into two groups: 148 with transmural myocardial infarction (group 1) and 40 with nontransmural myocardial infarction (group 2). Of the patients who survived hospitalization, follow-up data were obtained on 119 of 124 patients in group 1 and 36 of 37 patients in group 2 at a mean follow-up period of 36 months. In group 2, the patients had a high incidence of sudden death after discharge (33 per cent in group 2 versus 15 per cent in group 1, p < 0.02) as well as a significantly higher incidence of death from all cardiac causes (41.6 per cent in group 2 versus 24.3 per cent in group 1, p < 0.05). Furthermore, the patients in group 2 still alive at the end of the follow-up period had an increased incidence of angina pectoris and of recurrent infarction. The data suggest that patients with nontransmural myocardial infarction carry a particularly guarded prognosis.