The aberrant transformation of normal cells into cancer cells, known as carcinogenesis, is a complex process involving numerous genetic and molecular alterations in response to innate and environmental stimuli. The Src family kinases (SFK) are key components of signaling pathways implicated in carcinogenesis, with c-Src and its oncogenic counterpart v-Src often playing a significant role. The discovery of c-Src represents a compelling narrative highlighting groundbreaking discoveries and valuable insights into the molecular mechanisms underlying carcinogenesis. Upon oncogenic activation, c-Src activates multiple downstream signaling pathways, including the PI3K-AKT pathway, the Ras-MAPK pathway, the JAK-STAT3 pathway, and the FAK/Paxillin pathway, which are important for cell proliferation, survival, migration, invasion, metastasis, and drug resistance. In this review, we delve into the discovery of c-Src and v-Src, the structure of c-Src, and the molecular mechanisms that activate c-Src. We also focus on the various signaling pathways that c-Src employs to promote oncogenesis and resistance to chemotherapy drugs as well as molecularly targeted agents.

Obesity is a global menace that has impacted more than 14% of adults worldwide and more than a third of Americans. Importantly, obesity is associated with an increased risk of more than 13 types of cancer and worse outcomes, including increased mortality. This review focuses on the importance of considering obesity and metabolic dysfunction in cancer risk as part of the NCI’s funded consortium known as the Metabolic Dysfunction and Cancer Risk Program. It describes previous and ongoing mouse models used in studies conducted by Metabolic Dysfunction and Cancer Risk Program consortium members, as well as other relevant studies. Most cancer studies examine tumor progression, metastasis, or recurrence, which are consequences following tumor onset; however, this approach does not consider risk per se. To truly model cancer risk, parameters to measure include the quantification of cancer onset, measured as incidence or latency. Investigators must be cognizant of many factors in study design, including the choice of cancer model and genetic strain. Preclinical approaches addressing risk typically include genetically engineered mouse models or the administration of irritants or carcinogens. We also discuss the transplantation of cells or tumors such as allografts or xenografts, with a focus on tumor rejection or regression to approximate cancer risk, not cancer progression. Herein, we highlight two cancers, breast and colorectal cancers, in which risk is associated with obesity and discussed varied murine model approaches, as well as key findings that explore cancer risk, prevention, or interception.

Background: Squamous cell carcinoma of head and neck (SCCHN) is a devastating disease with high morbidity and mortality and the 6th most common cancer worldwide. The 5-year relative survival for advanced-stage disease is below 50%, stressing the need for chemoprevention. In the current study, we investigated the chemopreventive efficacy of the combination of resveratrol and epigallocatechin gallate (EGCG). Methods: We used the 4-Nitroquinoline 1-oxide (4-NQO)-induced oral carcinogenesis model. C57BL/6 mice were exposed to drinking water containing 4-NQO for 10 weeks. From week 11, mice were treated with vehicle, resveratrol, EGCG and their combination until week 22. RNASeq, qPCR and in silico analysis were performed identifying differentially expressed genes and enriched pathways. Results: Resveratrol alone and in combination with EGCG significantly inhibited the number of visible lesions, whereas the number of microscopic lesions and lesion areas were significantly inhibited only by the combination. The expression of Ki-67 was also significantly inhibited in resveratrol and combination groups. Growth differentiation factor 15 (GDF15), Activation transcription factor 3 (ATF3) and several other genes associated with xenobiotic metabolism as significantly upregulated genes, with GDF15 being the most upregulated one. Furthermore, hallmarks of xenobiotic metabolism and several other anticancer pathways were enriched after treatment with resveratrol and the combination. Conclusions: Our data strongly demonstrate the chemopreventive potential of the combination of resveratrol and EGCG and pave the way for further clinical developments.

Actinomycin D (Act D) was the first FDA-approved anticancer antibiotic. However, its widespread application was hindered by dose-limiting toxicities. In the current study, we investigated the in vitro and in vivo anticancer efficacy of the combination of Act D with resveratrol. We found that the combination of Act D and resveratrol has better in vitro efficacy than any of the single agent. We also explored the underlying mechanism by investigating the activation of the p53 pathway. Consistent with the cell growth inhibition, Act D, resveratrol, and their combination activated p53 and induced the expression of p21, PUMA, and GDF15 mRNA and proteins. The combination had better effects than any of the single agents alone. Ablation of p53 significantly protected cells and confirmed p53-dependent expression of these genes. Finally, we investigated the in vivo efficacy of these agents and their combination using xenograft model. Act D, resveratrol, and their combination significantly inhibited the growth of xenografts. The in vivo efficacy was further supported by Ki-67 expression in tumor tissues. Taken together, our findings demonstrated that although the combination of Act D and resveratrol showed better efficacy in vitro than any of the single agent, the in vivo efficacy was not improved.