In general cognition, metastasis happens in a relatively late stage of tumor progression. This may be true for most of the clinically-diagnosed tumor metastases. However, in rare cases, physicians have found lung metastases of breast cancer origin without (maybe ‘before’ is a better word here?) identification of the primary tumor. What is the etiology behind these infrequent cases?
A study by the Harold Varmus group from Memorial Sloan-Kettering Cancer Center (New York, NY) provided some insights. They took advantage of a strain of transgenic mice model carrying inducible oncogenes: MYC and k-Ras. Mammary cells from those transgenic mice were separated and systemically injected into recipients. When Myc and k-Ras were turned on a, metastatic tumors in the lungs were clearly identified, without primary tumors in breast! Even more amazing, even though the oncogenes in the injected mammary cells were silent, the cells were still able to reside and grow in lung! The logic speculation is: circulating mammary cells can “home” to the lung, reside in it and grow up a little bit, when the oncogenes are still being expressed. Those cells undergo hyperproliferation and then form “metastasis” tumors without primary tumor formation. Their results shed some light on the questions raised by clinicians about findings of metastases without primary tumor. So, it seems like mammary cells (normal or mutated) can circulate, or just reside in the lung and when the “malignant program” turns on, manifest like a metastatic cancer.
Actually, breast cancer xenograft mouse model can produce multi-organ metastases, such as lung, brain and bone metastases, etc. In the paper, they didn’t identify any significant metastasis other than lung. Then I’d like to look at an important issue of “homing”. In metastasis of the breast carcinoma, Carcinoma-Associated Fibroblast (CAF) secretes Stroma-Derived Factor 1 (SDF-1)/CXCL12, which directly interacts with its receptor on breast cancer cells, CXCR4, and directs tumor cell migration, as shown in the picture below.
Schematic representation of tumor-promoting effects provoked by CAFwithin invasive human mammary carcinomas (credit: Akira Orimo & Robert Weinberg, Cell Cycle 2006;5;15:1597)
Varmus group injected mice with temporarily normal mammary cells, which may not be ready to express CXCR4 and obviously without the help of CAF. But we don’t know why the lung may be their favorite final stop.
Metastasis is the major cause for cancer mortality and attracts most interests from clinicians. As early as 1889, Steven Paget proposed a theory of “seed” and “soil” for breast cancer and bone metastasis. Rohr and Hegglin physically observed breast metastasis cancer cells in bone marrow biopsies from clinically diagnosed metastatic cases. Then the concept of micro-metastasis was brought forward by indentification of single metastatic tumor cell in bone marrow from clinically non-metastatic breast cancer patients. Those traveling cancer cells are called Disseminated Tumor cells (DTC) and Circulating Tumor Cells (CTC). However, only 50% of patients with DTCs eventually developed clinically diagnosed metastatic cancer. The other astonishing fact about DTC and CTC is that some cell markers, may not necessarily be identical to their primary counterparts. Now we know DTC and CTC are bona-fide avant-garde of breast cancers and the next question is how to take advantage of them for diagnosis and treatment.
This paper left us several pivotal questions about cancer metastasis development and normal cell migration. Why and how do mammary cells decide to stay in lung instead of mammary tissue? How many tissue cells are circulating in our body daily? How we can identify those travelers and apply our knowledge for metastases prevention?