SummaryIn cancer treatment, apoptosis is a well-recognized cell death mechanism through which cytotoxic agents kill tumor cells. Here we report that dying tumor cells use the apoptotic process to generate potent growth-stimulating signals to stimulate the repopulation of tumors undergoing radiotherapy. Surprisingly, activated caspase 3, a key executioner of apoptosis, plays key roles in the growth stimulation. One downstream effector that caspase 3 regulates is prostaglandin E2, which can potently stimulates growth of surviving tumor cells. Deficiency of caspase 3 either in tumor cells or in tumor stroma caused significant tumor sensitivity to radiotherapy in xenograft or mouse tumors. In human cancer patients, higher levels of activated caspase 3 in tumor tissues are correlated with significantly increased rate of recurrence and deaths. We propose the existence of a “Phoenix Rising” pathway of cell death-induced tumor repopulation in which caspase 3 plays key roles.

Long-term exposure to excess estrogen increases the risk of breast cancer and type 1 endometrial cancer. Most of the estrogen in premenopausal women is synthesized by the ovaries, while extraovarian subcutaneous adipose tissue is the predominant tissue source of estrogen after menopause. Estrogen and its metabolites can cause hyperproliferation and neoplastic transformation of breast and endometrial cells via increased proliferation and DNA damage. Several genetically modified mouse models have been generated to help understand the physiological and pathophysiological roles of aromatase and estrogen in the normal breast and in the development of breast cancers. Aromatase, the key enzyme for estrogen production, is comprised of at least ten partially tissue-selective and alternatively used promoters. These promoters are regulated by distinct signaling pathways to control aromatase expression and estrogen formation via recruitment of various transcription factors to their cis-regulatory elements. A shift in aromatase promoter use from I.4 to I.3/II is responsible for the excess estrogen production seen in fibroblasts surrounding malignant epithelial cells in breast cancers. Targeting these distinct pathways and/or transcription factors to modify aromatase activity may lead to the development of novel therapeutic remedies that inhibit estrogen production in a tissue-specific manner.

The multilineage differentiation potential of human umbilical cord mesenchymal stem cells (HUCMSCs) holds therapeutic promise for non-healing ulcers and tissue regeneration. The present study evaluated the effects of HUCMSC transplantation after angioplasty for treatment of diabetic foot. Included in the study were 53 patients (72 limbs) with severe symptoms of Fontaine II-IV diabetic foot accompanied by varying degrees of lower extremity arterial disease. The patients were randomly apportioned to a control group (25 patients; 38 limbs) or an experimental group (28 patients; 34 limbs). Patients of both groups received interventional treatment with angioplasty; those in the experimental group also received HUCMSCs by endovascular infusion and injection around the foot ulcer. Within the 3-month follow-up, relative to patients in the control group, those in the experimental group experienced significantly greater and more stable improvements in skin temperature, ankle-brachial pressure index, transcutaneous oxygen tension, and claudication distance. Notably, 3 months after treatment a significant increase in neovessels, accompanied by complete or gradual ulcer healing, was shown in the experimental group. In addition, no serious complications or adverse reactions were associated with the treatment. Therefore, our results indicate that HUCMSC transplantation after angioplasty is a safe and effective clinical therapy for severe diabetic foot.

DNA double-strand breaks (DSBs) are traditionally associated with cancer through their abilities to cause chromosomal instabilities or gene mutations. Here we report a new class of self-inflicted DNA DSBs that can drive tumor growth irrespective of their effects on genomic stability. We discover a mechanism through which cancer cells cause DSBs in their own genome spontaneously independent of reactive oxygen species or replication stress. In this mechanism, low-level cytochrome c leakage from the mitochondria leads to sublethal activation of apoptotic caspases and nucleases, which causes DNA DSBs. In response to these spontaneous DNA DSBs, ATM, a key factor involved in DNA damage response, is constitutively activated. Activated ATM leads to activation of transcription factors NF-κB and STAT3, known drivers of tumor growth. Moreover, self-inflicted DNA DSB formation and ATM activation are important in sustaining the stemness of patient-derived glioma cells. In human tumor tissues, elevated levels of activated ATM correlate with poor patient survival. Self-inflicted DNA DSBs therefore are functionally important for maintaining the malignancy of cancer cells.