28 June 2013
Lately I’ve been reading up on circulating tumor cells: cells that are from the tumor(s) of a cancer patient that wind up in the blood. For instance: a breast cancer patient might have cells in the blood that originated from normal cells lining milk ducts in the breast, that evolved into a breast tumor, that then escaped the tumor to reach the bloodstream. These cells are the seeds of the most malicious and crippling part of the disease: metastasis.
It’s been widely estimated that 90% of cancer mortality comes from metastases, not necessarily the primary tumor (1) and it’s been known since the late 19th century that surgical interventions are much more successful at curing patients when the tumor is intact and in one place (2).
The image to right is a PET scan of a 46 year old woman with malignant melanoma. Dark regions (minus the bladder) are regions of tumor burden, and most of it are metastases. There are tumors in her lungs, skin, liver, speen, and many lymph nodes. For a moment, try to imagine being a surgeon tasked with removing as many as possible with your scalpel…
Disseminated cancer is very hard to treat; it’s a moving target in the most literal sense. HOW it spreads has been a preoccupation of mine for the better part of a decade. If it were possible to stop the advance of cancer spread in a patient, it might be possible to make cancer a chronic condition rather than a death sentence.
Circulating tumor cells (CTC’s) are the seeds of cancer in the wind: the spores of malignancy.
In one milliliter of blood (about the volume up to the first joint of a human pinky) there are roughly 9 billion (9,000,000,000) red blood cells. (source) In contrast, in advanced cancer patients there might be one CTC in that volume.
Astonishingly, there are technologies that can detect these rare cells with great accuracy. In a seminal paper in 2004, Allard et al demonstrated a re-capture rate of more than 90% when blood from healthy volunteers was spiked with known quantities of cancer cells (3). These technologies have been refined to the point that it is now possible to characterize individual CTC’s (4, 5)
The number of CTC’s gives a strong proxy for prognosis, with the field setting a threshold of 5 CTC’s per 7.5ml of blood as a negative prognostic factor for survival (4, 6, 7). In contrast, healthy volunteers seldom had cells that were captured as CTC’s, indicating a low false positive rate.
Such information could be very useful in the clinic, and number of CTC’s have been demonstrated in patients to predict cancer recurrence and drug resistance too (5). It may be possible to use CTC counts as a biomarker for tumor burden in general.
Despite their rare nature, the number of CTC’s that form tumors is extremely low. Most of the seeds do not survive and form new tumors. Even if a patient only has 5 CTC’s per 7.5ml of blood, that would reflect a moment in time where more than 3000 CTC’s were present in a patient. As would be conceptually predicted for cells not adapted to the sheer forces of the circulatory system, it was interesting to read about shards and pieces of CTC’s being detected as well in cancer patients (3).
Molecular analysis of CTC’s revealed a large heterogeneity in gene expression between individual CTC’s in the same patient (4). While this is somewhat daunting from a targeted therapy standpoint, the coming age of cheap genetic sequencing might enable us to view a macro scale of gene expression and correlation to patient survival in large populations. Such insights might make it possible to specifically target the dangerous CTC’s in the blood, and destroy the seeds in transit before they form metastases.
Based off the available information, it appears that CTC’s might be useful for tracking the disease progression of cancer patients. Genetic profiling of these cells with emerging technologies might give intimate glimpses into the basic biology of cancer spread. However, the amount of blood needed (7.5ml) and the fragile nature of blood outside the body makes me doubt its efficacy for early detection of cancer. Nonetheless, I will be following developments in this field with great interest.
Ryon
References:
1. Gupta GP, Massague J. Cancer metastasis: building a framework. Cell. 2006 Nov 17;127(4):679-95. PubMed PMID: 17110329. Epub 2006/11/18. eng. 2. Mukherjee, S. The Emperor of all Maladies. 2010. 3. Allard WJ, Matera J, Miller MC, Repollet M, Connelly MC, Rao C, et al. Tumor cells circulate in the peripheral blood of all major carcinomas but not in healthy subjects or patients with nonmalignant diseases. Clinical cancer research : an official journal of the American Association for Cancer Research. 2004 Oct 15;10(20):6897-904. PubMed PMID: 15501967. Epub 2004/10/27. eng. 4. Powell AA, Talasaz AH, Zhang H, Coram MA, Reddy A, Deng G, et al. Single cell profiling of circulating tumor cells: transcriptional heterogeneity and diversity from breast cancer cell lines. PloS one. 2012;7(5):e33788. PubMed PMID: 22586443. Pubmed Central PMCID: PMC3346739. Epub 2012/05/16. eng. 5. Marchesi V. Breast cancer: Epithelial-mesenchymal transitions in human breast cancer samples. Nature reviews Clinical oncology. 2013 Apr;10(4):184. PubMed PMID: 23419957. Epub 2013/02/20. eng. 6. Cristofanilli M, Budd GT, Ellis MJ, Stopeck A, Matera J, Miller MC, et al. Circulating tumor cells, disease progression, and survival in metastatic breast cancer. The New England journal of medicine. 2004 Aug 19;351(8):781-91. PubMed PMID: 15317891. Epub 2004/08/20. eng. 7. Liu MC, Shields PG, Warren RD, Cohen P, Wilkinson M, Ottaviano YL, et al. Circulating tumor cells: a useful predictor of treatment efficacy in metastatic breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2009 Nov 1;27(31):5153-9. PubMed PMID: 19752342. Epub 2009/09/16. eng.